Thiazole derivatives as phosphodiesterase IV inhibitors

ABSTRACT

Thiazole derivatives of the formula I 
                         
in which R 1 , R 2 , R 3 , V, W, X and B are as defined in claim  1 , act as phosphodiesterase IV inhibitors and can be employed for the treatment of osteoporosis, tumors, cachexia, atherosclerosis, rheumatoid arthritis, multiple sclerosis, diabetes mellitus, inflammatory processes, allergies, asthma, autoimmune diseases, myocardial diseases and AIDS.

The invention relates to compounds of the formula I

in which

-   R¹ and R² are each, independently of one another, H, OH, OR⁸, —SR⁸,    —SOR⁸, —SO₂R⁸ or Hal,-   R¹ and R² together are alternatively —OCH₂O— or —OCH₂CH₂O—,-   R³ and R^(3′) are each, independently of one another; H, A″R⁷,    COA″R⁷, COOA″R⁷, CONH₂, CONHA″R⁷, CON(A″R⁷)(A′″R⁷), CONR¹⁰Het, NH₂,    NHA″R⁷, N(A″R⁷)(A′″R⁷), NCOA″R⁷ or    -   NCOOA″R⁷,-   V and W are oxygen or hydrogen substituents, with the proviso that,    if V is O, W is H,H,    -   and vice versa,-   B is an aromatic isocyclic or heterocyclic radical, which may be    unsubstituted or monosubstituted, disubstituted or trisubstituted by    R⁴, R⁵ and/or R⁶,-   X is N or CR^(3′),-   R⁴, R⁵-   and R⁶ are each, independently of one another, H, A″R⁷, OH, OA″R⁷,    NO₂, NH₂, NHA″R⁷, N(A″R⁷)(A′″R⁷), NHCOA″R⁷, NHCOOA″R⁷, NHCONH₂,    NHCONHA″R⁷,    -   NHCON(A″R⁷)(A′″R⁷), Hal, COOH, COOA″R⁷, CONH₂, CONHA″R⁷,        CON(A″R⁷)(A′″R⁷),

-   R⁷ is H, COOH, COOA, CONH₂, CONHA, CONAA′, NH₂, NHA, NAA′, NCOA,    NCOOA, OH or OA,-   R⁸ is A, cycloalkyl having 3-7 carbon atoms, alkylenecycloalkyl    having 4-8 carbon atoms or alkenyl having 2-8 carbon atoms,-   R⁹ is alkyl having 1-10 carbon atoms, cycloalkyl having 3-7 carbon    atoms, alkylenecycloalkyl having 4-8 carbon atoms or alkenyl having    2-8 carbon atoms,    -   in which one, two or three CH₂ groups may be replaced by O, S,        SO, SO₂, NH, NMe, NEt and/or by —CH═CH— groups, and/or    -   1-7 H atoms may be replaced by F and/or Cl,-   Y is alkylene having 1-10 carbon atoms or alkenylene having 2-8    carbon atoms,    -   in which one, two or three CH₂ groups may be replaced by O, S,        SO, SO₂, NH or NR⁹ and/or    -   1-7 H atoms may be replaced by F and/or Cl,-   A and A′ are each, independently of one another, alkyl having 1-10    carbon atoms or alkenyl having 2-8 carbon atoms,    -   in which one, two or three CH₂ groups may be replaced by O, S,        SO, SO₂, NH or NR⁹ and/or    -   1-7 H atoms may be replaced by F and/or Cl, or    -   aryl or Het,-   A and A′ together are alternatively an alkylene chain having 2-7    carbon atoms, in which one, two or three CH₂ groups may be replaced    by O, S, SO, SO₂, NH, NR⁹, NCOR⁹ or NCOOR⁹,-   A″ and A′″ are each, independently of one another, absent, alkylene    having 1-10 carbon atoms, alkenylene having 2-8 carbon atoms or    cycloalkylene having 3-7 carbon atoms,    -   in which one, two or three CH₂ groups may be replaced by O, S,        SO, SO₂, NH or NR⁹ and/or    -   1-7 H atoms may be replaced by F and/or Cl,-   A″ and A′″ together are alternatively an alkylene chain having 2-7    carbon atoms, in which one, two or three CH₂ groups may be replaced    by O, S, SO, SO₂, NH, NR⁹, NCOR⁹ or NCOOR⁹,-   aryl is phenyl, naphthyl, fluorenyl or biphenyl, each of which is    unsubstituted or monosubstituted, disubstituted or trisubstituted by    Hal, R¹¹, OR¹⁰, N(R¹⁰)₂, NO₂, CN, COOR¹⁰,    -   CON(R¹⁰)₂, NR¹⁰COR¹⁰, NR¹⁰CON(R¹⁰)₂, NR¹⁰SO₂A, COR¹⁰, SO₂N(R¹⁰)₂        or S(O)_(m)R¹¹,-   R¹⁰ is H or alkyl having 1-6 carbon atoms,-   R¹¹ is alkyl having 1-6 carbon atoms,-   Het is a monocyclic or bicyclic saturated, unsaturated or aromatic    heterocyclic ring having 1 or 2 N, O and/or S atoms, which may be    unsubstituted or monosubstituted or disubstituted by carbonyl    oxygen, Hal, R¹¹, OR¹⁰, N(R¹⁰)₂, NO₂, CN, COOR¹⁰, CON(R¹⁰)₂,    NR¹⁰COR¹⁰, NR¹⁰CON(R¹⁰)₂, NR¹⁰SO₂R¹¹, COR¹⁰, SO₂NR¹⁰ and/or    S(O)_(m)R¹¹,-   Hal is F, Cl, Br or I,-   m is 0, 1 or 2,    and pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios.

1-Benzoyltetrahydropyridazines as progesterone receptor ligand aredescribed, for example, in J. Med. Chem. 38, 4878 (1995). Furtherarylalkanoylpyridazines are disclosed, for example, in EP 0 922 036, EP1 124 809 or WO 01/04099.

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the production ofmedicaments.

It has been found that the compounds of the formula I and their saltshave very valuable pharmacological properties and are well tolerated. Inparticular, they exhibit specific inhibition of “rolipram insensitive”cAMP phosphodiesterase (PDE VII).

The compounds of the formula I exhibit selective phosphodiesterase IVinhibition which is associated with an intracellular increase of cAMP(N. Sommer et al., Nature Medicine, 1, 244-248 (1995)). The PDE IVinhibition can be detected, for example, analogously to C. W. Davis inBiochim. Biophys. Acta 797, 354-362 (1984).

The affinity of the compounds according to the invention forphosphodiesterase IV is determined by measuring their IC₅₀ values(concentration of the inhibitor that is required in order to achieve50%. inhibition of the enzyme activity).

The compounds according to the invention can be employed for thetreatment of asthmatic diseases. The anti-asthmatic action of the PDE IVinhibitors has been described, for example, by T. J. Torphy et al. inThorax, 46, 512-523 (1991), and can be determined, for example, by themethod of T. Olsson, Acta allergologica 26, 438-447 (1971).

Since cAMP inhibits osteoclastic cells and stimulates osteogenetic cells(S. Kasugai et al., M 681, and K. Miyamoto, M 682, in Abstracts of theAmerican Society for Bone and Mineral Research, 18^(th) Annual Meeting,1996), the compounds according to the invention can be employed for thetreatment of osteoporosis.

In addition, the compounds exhibit an antagonistic action to theproduction of TNF (tumour necrosis factor) and are therefore suitablefor the treatment of allergic and inflammatory diseases, autoimmunediseases, such as, for example, rheumatoid arthritis, multiplesclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis,transplant rejection reactions, cachexia and sepsis.

The anti-inflammatory action of the substances according to theinvention and their effectiveness for the treatment of, for example,autoimmune diseases, such as multiple sclerosis or rheumatoid arthritiscan be determined analogously to the methods of N. Sommer et al., NatureMedicine 1, 244-248 (1995), or L. Sekut et al., Clin. Exp. Immunol. 100,126-132 (1995).

The compounds can be employed for the treatment of cachexia. Theanti-cachectic action can be tested in TNF-dependent models of cachexia(P. Costelli et al., J. Clin. Invest. 95, 2367 ff. (1995); J. M. Argileset al., Med. Res. Rev. 17, 477 ff. (1997)).

PDE IV inhibitors can also inhibit the growth of tumour cells and aretherefore suitable for tumour therapy (D. Marko et al., Cell Biochem.Biophys. 28, 75 ff. (1998)). The action of PDE IV inhibitors in thetreatment of tumours is described, for example, in WO 95/35281, WO95/17399 or WO96/00215

PDE IV inhibitors can prevent mortality in models of sepsis and aretherefore suitable for the therapy of sepsis (W. Fischer et al.,Biochem. Pharmacol. 45, 2399ff. (1993)).

They can furthermore be employed for the treatment of memory disorders,atherosclerosis, atopical dermatitis and AIDS.

The action of PDE IV inhibitors in the treatment of asthma, inflammatorydisorders, diabetes mellitus, atopic dermatitis, psoriasis, AIDS,cachexia, tumour growth or tumour metastases is described, for example,in EP 77 92 91.

The compounds of the formula I can be employed as pharmaceutical activecompounds in human and veterinary medicine. They can furthermore beemployed as intermediates for the preparation of further pharmaceuticalactive compounds.

Furthermore, the invention relates to the use of type 4phosphodiesterase inhibitors (PDE IV inhibitors) of the formula I totreat diseases and relates to combinations of compounds of the formula Iwith other medicaments.

Reference is made to WO 01/57025 which discloses special pyrimidinederivatives as PDE IV inhibitors, their use for treating diseases andcombinations with other medicaments.

Accordingly, the invention provides in particular for the use ofcompounds of the formula I and their physiologically acceptable saltsand solvates for preparing a medicament for treating a subject sufferingfrom a disease or condition mediated by the PDE IV isozyme in its roleof regulating the activation and degranulation of human eosinophils.

WO 01/57025 discloses various in vitro assays and animal modelexperiments, which are capable of providing data sufficient to defineand demonstrate therapeutic utility of compounds of the formula I.

Compounds of the formula I inhibit the PDE IV isozyme and thereby have awide range of therapeutic applications, because of the essential rolewhich the PDE IV family of isozymes plays in the physiology of allmammals. The enzymatic role performed by the PDE IV isozymes is theintracellular hydrolysis of adenosine 3′, 5′-monophosphate (cAMP) withinproinflammatory leukocytes. cAMP, in turn, is responsible for mediatingthe effects of numerous hormones in the body, and as a consequence, PDEIV inhibition plays a significant role in a variety of physiologicalprocesses. There is extensive literature in the art describing theeffects of PDE inhibitors on various inflammatory cell responses, whichin addition to cAMP elevation, include inhibition of superoxideproduction, degranulation, chemotaxis and tumour necrosis factor (TNF)release in eosinophils, neutrophils and monocytes.

The invention therefore relates to the compounds of the formula I and toa process for the preparation of compounds of the formula I and saltsand solvates thereof, characterised in that

-   a) for the preparation of a compound of the formula I in which V is    H,H and W is O,-   a compound of the formula II

-   in which-   R¹ and R² are as defined in claim 1, is reacted with a compound of    the formula III

-   in which-   L is Cl, Br, I or a free or reactively functionally modified OH    group,-   and R³, X and B are as defined in claim 1,-   with the proviso that any further OH and/or amino group present is    protected,-   and subsequently, if desired, a protecting group is removed,-   and/or-   b) one or more radicals R¹, R², R³ and/or B in a compound of the    formula I are converted into one or more other radicals R¹, R², R³    and/or B by-   i) cleaving an ether or ester,-   ii) alkylating or acylating an OH function,-   iii) reductively alkylating an amino group,-   iv) reacting an amino group with malononitrile,-   v) converting a cyano group into a tetrazole group,-   and/or in that a basic compound of the formula I is converted into    one of its salts by treatment with an acid.

In addition, the invention relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds. The term solvates of thecompounds is taken to mean adductions of inert solvent molecules ontothe compounds which form owing to their mutual attractive force.Solvates are, for example, monohydrates, dihydrates or alcoholates.

The term pharmaceutically usable derivatives is taken to mean, forexample, the salts of the compounds according to the invention andso-called prodrug compounds.

The term prodrug derivatives is taken to mean, for example, compounds ofthe formula I which have been modified, for example, with alkyl or acylgroups, sugars or oligopeptides and which are rapidly cleaved in theorganism and thus release the active ingredients according to theinvention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The following abbreviations are used below:

-   Ac acetyl-   BOC tert-butoxycarbonyl-   CBZ or Z benzyloxycarbonyl-   DCCI dicyclohexylcarbodiimide-   DCM dichloromethane-   DMF dimethylformamide-   EA ethyl acetate-   EDCI N-ethyl-N,N′-(dimethylaminopropyl)carbodiimide-   Et ethyl-   Fmoc 9-fluorenylmethoxycarbonyl-   HOBt 1-hydroxybenzotriazole-   Me methyl-   MBHA 4-methylbenzhydrylamine-   Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl-   HONSu N-hydroxysuccinimide-   OBut tert-butyl ester-   Oct octanoyl-   OMe methyl ester-   OEt ethyl ester-   POA phenoxyacetyl-   TFA trifluoroacetic acid-   Trt trityl (triphenylmethyl).

The meanings of all radicals which occur more than once are in each caseindependent of one another.

Above and below, the radicals R¹, R², R³, V, W, X, B and L are asdefined in the formulae I, II and III, unless expressly statedotherwise.

Alkyl having 1-10 carbon atoms is alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9or 10 carbon atoms, is branched or unbranched, and is preferably alkylhaving 1, 2, 3, 4, 5 or 6 carbon atoms and is, for example, methyl,ethyl, trifluoromethyl, pentafluoroethyl or propyl, furthermorepreferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but alson-pentyl, neopentyl, isopentyl or n-hexyl. Particular preference isgiven to methyl, ethyl, trifluoromethyl, propyl, isopropyl, butyl,n-pentyl, n-hexyl or n-decyl.

Cycloalkyl preferably has 3-7 carbon atoms and is preferably cyclopropylor cyclobutyl, furthermore preferably cyclopentyl or cyclohexyl,furthermore also cycloheptyl; particular preference is given tocyclopentyl.

Alkenyl is preferably vinyl, allyl, 2- or 3-butenyl, isobutenyl orsec-butenyl; preference is furthermore given to 4-pentenyl, isopentenylor 5-hexenyl.

Alkylene is preferably unbranched and is preferably methylene orethylene, furthermore preferably propylene or butylene.

Alkylenecycloalkyl is, for example, cyclohexylmethyl orcyclopentylethyl.

Alkyl having 1-6 carbon atoms is alkyl having 1, 2, 3, 4, 5 or 6 carbonatoms, is branched or unbranched, and is, for example, methyl, ethyl,trifluoromethyl, pentafluoroethyl or propyl, furthermore preferablyisopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl,neopentyl, isopentyl or n-hexyl. Particular preference is given tomethyl, ethyl, trifluoromethyl, propyl, isopropyl, butyl, n-pentyl orn-hexyl.

Hal is preferably F, Cl or Br, furthermore also I.

The radicals R¹ and R² may be identical or different and are preferablyin the 3- or 4-position of the phenyl ring. They are, for example,independently of one another, H, hydroxyl, —S—CH₃, —SO—CH₃, —SO₂CH₃, F,Cl, Br or I or together are methylenedioxy. However, they are preferablyeach methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy,benzyloxy, or alternatively fluoro-, difluoro- or trifluoromethoxy or1-fluoro-, 2-fluoro-, 1,2-difluoro-, 2,2-difluoro-, 1,2,2-trifluoro- or2,2,2-trifluoroethoxy.

In a further embodiment, R¹ and R² are each, independently of oneanother, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms.

Alkoxy has 1, 2, 3, 4, 5 or 6 carbon atoms and is, for example, methoxy,ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexoxy, cyclopentyloxy orcyclohexyloxy.

In a further embodiment, R¹ and R² are each, independently of oneanother, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms.

Alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,pentoxy or hexoxy.

R¹ is particularly preferably ethoxy, benzyloxy, F, propoxy orisopropoxy, furthermore difluoromethoxy or cycloalkoxy, for examplecyclopentoxy. R¹ is very particularly preferably 4-methoxy or 4-ethoxy.

R² is particularly preferably methoxy, ethoxy, propoxy, F or ethyl,furthermore difluoromethoxy or cycloalkoxy, for example cyclopentoxy.

R² is very particularly preferably 3-methoxy, 3-ethoxy, 3-propoxy,3-isopropoxy or 3-cyclopentyloxy.

R³ is preferably H, A″R⁷, COA″R⁷, CON(A″R⁷)(A′″R⁷) or CO—NR¹⁰-Het,particularly preferably H or A″R⁷.

In a further embodiment, R³ is preferably, for example, H, COOH,CO—CH₂—NAA′, CO—CH₂—CH₂—NAA′, CO—CH₂—NHA′ or CO—CH₂—CH₂—NHA′.

R^(3′) is particularly preferably H.

X is preferably N or CH, very particularly preferably N.

B is an aromatic isocyclic radical, such as, for example, phenyl,naphthyl, fluorenyl or biphenyl, or a heterocyclic radical, where theradicals are unsubstituted or may be monosubstituted, disubstituted ortrisubstituted by R⁴, R⁵ and/or R⁶, and where the heterocyclic radicalis preferably a monocyclic saturated or unsaturated heterocycle having 1or 2 N, O and/or S atoms.

B is preferably phenyl, pyridyl, pyridyl N-oxide, thienyl, furyl,pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoxazolinyl,oxazolinyl, thiazolinyl, pyrazolinyl, imidazolinyl, naphthyl,quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl orquinoxalinyl, each of which is unsubstituted or may be monosubstituted,disubstituted or trisubstituted by R⁴, R⁵ and/or R⁶.

In a further preferred embodiment, B is phenyl, pyridyl, pyridylN-oxide, thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazinyl, isoxazolinyl, oxazolinyl, thiazolinyl, pyrazolinyl,imidazolinyl, naphthyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl or quinoxalinyl, each of which isunsubstituted or may be monosubstituted, disubstituted or trisubstitutedby OH, OA, NO₂, NH₂, NAA′,

In a further preferred embodiment, B is unsubstituted pyridyl, pyridylN-oxide, thienyl or pyrazinyl.

R⁴, R⁵ and R⁶ are preferably H.

R⁷ is preferably H, COOH, NHA or NAA′, very particularly preferably H.

R⁸ is preferably R¹¹, cycloalkyl having 3-7 carbon atoms oralkylenecycloalkyl having 4-8 carbon atoms.

R⁹ is preferably alkyl having 1-10 carbon atoms, very particularlypreferably alkyl having 1-6 carbon atoms.

Y is preferably methylene, ethylene, propylene or butylene.

A and A′ are preferably each, independently of one another, alkyl having1-10 carbon atoms, in which 1-7 H atoms may be replaced by F and/or Cl,or are each, independently of one another, aryl or Het.

A″ and A′″ are preferably each, independently of one another: absent oralkylene having 1-10 carbon atoms, in which one CH₂ group may bereplaced by NH or NR⁹.

A″ and A′″ are preferably together alternatively an alkylene chainhaving 2-7 carbon atoms, in which one CH₂ group may be replaced by NH orNR⁹.

Aryl is, for example, unsubstituted phenyl, naphthyl, fluorenyl orbiphenyl, furthermore preferably phenyl, naphthyl, fluorenyl orbiphenyl, each of which is monosubstituted, disubstituted ortrisubstituted, for example, by methyl, ethyl, propyl, butyl, fluorine,chlorine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy,hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl,amino, methylamino, ethylamino, dimethylamino, diethylamino,sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido,butylsulfonamido, dimethylsulfonamido, carboxyl, methoxycarbonyl,ethoxycarbonyl or aminocarbonyl.

Het is, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-,4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl,furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-,-3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl,1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or5-isoindolyl, 1-, 2-, 4-, or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or7-benzopyrazolyl, 2-, 4-, .5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-,5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-,4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benz-1,4-oxazinyl,furthermore preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals may also be partially or completelyhydrogenated.

Het can thus also be, for example, 2,3-dihydro-2-, -3-, 4- or -5-furyl,2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl,1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-,-3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, 4- or -5-pyrrolyl,1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or-4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl,1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-l-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1 -, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, 4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benz-1,4-oxazinyl, furthermore preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or -6-yl,2,3-(2-oxomethylenedioxy)phenyl or 3,4-dihydro-2H-1,5-benzodioxepin-6-or -7-yl, furthermore preferably 2,3-dihydrobenzofuranyl or2,3-dihydro-2-oxofuranyl.

In a further embodiment, Het is particularly preferably unsubstitutedpyridyl, pyridyl N-oxide, thienyl, furyl, pyrrolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, isoxazolinyl, oxazolinyl,thiazolinyl, pyrazolinyl, imidazolinyl, naphthyl, quinolinyl,isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl or quinoxalinyl,very particularly preferably pyridyl.

In a further preferred embodiment, Het is a monocyclic saturated orunsaturated heterocyclic ring having 1 or 2 N and/or O atoms, which maybe monosubstituted or disubstituted by carbonyl oxygen, OH or OA. Hettherein is particularly preferably, for example, 2-oxopiperidin-1-yl,2-oxopyrrolidin-1-yl, 2-oxo-1H-pyridin-1-yl, 3-oxomorpholin-4-yl,4-oxo-1H-pyridin-1-yl, 2,6-dioxopiperidin-1-yl, 2-oxopiperazin-1-yl,2,6-dioxopiperazin-1-yl, 2,5-dioxopyrrolidin-1-yl,2-oxo-1,3-oxazolidin-3-yl, 3-oxo-2H-pyridazin-2-yl, 2-caprolactam-1-yl(=2-oxoazepan-1-yl), 2-hydroxy-6-oxopiperazin-1-yl,2-methoxy-6-oxopiperazin-1-yl, 2-azabicyclo[2.2.2]-octan-3-on-2-yl, veryparticularly preferably 2-oxopiperidin-1-yl.

n is preferably 0 or 1.

In a further embodiment, Het is very particularly preferably amonocyclic saturated heterocyclic radical having 1 or 2 N atoms, whichmay be monosubstituted or disubstituted by alkyl having 1-6 carbonatoms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings given above. Some preferred groups of compounds maybe expressed by the following sub-formulae la to In, which conform tothe formula I and in which the radicals not denoted in greater detailare as defined for the formula I, but in which

-   in Ia R¹ and R² are each, independently of one another, alkoxy    having 1, 2, 3, 4, 5 or 6 carbon atoms;-   in Ib R¹ and R² are each, independently of one another, H, methoxy,    ethoxy, benzyloxy, propoxy, isopropoxy, difluoromethoxy, F, Cl,    cyclopentyloxy, cyclohexyloxy or cycloheptyloxy;-   in Ic R¹ and R² are each, independently of one another, methoxy,    ethoxy, propoxy, isopropoxy, cyclopentyloxy or F;-   in Id R¹ is 4-methoxy or 4-ethoxy,    -   R² is 3-methoxy, 3-ethoxy, 3-propoxy, 3-isopropoxy or        3-cyclopentyloxy;-   in Ie R³ is H or A″R⁷;-   in If X is N or CH;-   in Ig B is an aromatic isocyclic or monocyclic saturated or    unsaturated heterocyclic ring having 1 or 2 N, O and/or S atoms;-   in Ih B is phenyl, pyridyl, pyridyl N-oxide, thienyl, furyl,    pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,    isoxazolinyl, oxazolinyl, thiazolinyl, pyrazolinyl, imidazolinyl,    naphthyl, quinolinyl, isoquinolinyl, cinnolinyl,    -   phthalazinyl, quinazolinyl or quinoxalinyl, each of which is        unsubstituted or may be monosubstituted, disubstituted or        trisubstituted by R⁴, R⁵ and/or R⁶;-   in Ii B is phenyl, pyridyl, pyridyl N-oxide, thienyl, furyl,    pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,    isoxazolinyl, oxazolinyl, thiazolinyl, pyrazolinyl, imidazolinyl,    naphthyl, quinolinyl, isoquinolinyl, cinnolinyl,    -   phthalazinyl, quinazolinyl or quinoxalinyl, each of which is        unsubstituted or may be monosubstituted, disubstituted or        trisubstituted by OH, OA, NO₂, NH₂, NAA′,

-   in Ij B is unsubstituted pyridyl, pyridyl N-oxide, thienyl or    pyrazinyl;-   in Ik R¹ and R² are each, independently of one another, alkoxy    having 1, 2, 3, 4, 5 or 6 carbon atoms,    -   X is N or CH,    -   R³ is H or A″R⁷,    -   A″ and A′″ are each, independently of one another, absent or        alkylene having 1-10 carbon atoms, in which one CH₂ group may be        replaced by NH or NR⁹,    -   A″ and A′″ together are alternatively an alkylene chain having        2-7 carbon atoms, in which one CH₂ group may be replaced by NH        or NR⁹,    -   B is phenyl, pyridyl, pyridyl N-oxide, thienyl, furyl, pyrrolyl,        pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoxazolinyl,        oxazolinyl, thiazolinyl, pyrazolinyl, imidazolinyl, naphthyl,        quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,        quinazolinyl or quinoxalinyl, each of which is unsubstituted or        may be monosubstituted, disubstituted or trisubstituted by OH,        OA, NO₂, NH₂, NAA′,

-   -   R⁷ is H, COOH, NHA or NAA′,    -   R⁹ is alkyl having 1-6 carbon atoms,    -   A and A′ are each, independently of one another, alkyl having        1-10 carbon atoms, in which 1-7 H atoms may be replaced by F        and/or Cl;

-   in Il R¹ is 4-methoxy or 4-ethoxy,    -   R² is 3-methoxy, 3-ethoxy, 3-propoxy, 3-isopropoxy or        3-cyclopentyloxy,    -   X is N,    -   R³ is H or alkyl having 1-6 carbon atoms,    -   B is phenyl, pyridyl, pyridyl N-oxide, thienyl, furyl, pyrrolyl,        pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoxazolinyl,        oxazolinyl, thiazolinyl, pyrazolinyl, imidazolinyl, naphthyl,        quinolinyl, isoquinolinyl, cinnolinyl,    -   phthalazinyl, quinazolinyl or quinoxalinyl, each of which is        unsubstituted or may be monosubstituted, disubstituted or        trisubstituted by OH, OA, NO₂, NH₂, NAA′,

-   -   R⁷ is H,    -   R⁹ is alkyl having 1-6 carbon atoms,    -   A and A′ are each, independently of one another, alkyl having        1-10 carbon atoms, in which 1-7 H atoms may be replaced by F        and/or Cl;

-   in Im R¹ is 4-methoxy or 4-ethoxy,    -   R² is 3-methoxy, 3-ethoxy, 3-propoxy, 3-isopropoxy or        3-cyclopentyloxy,    -   X is N,    -   R³ is H or alkyl having 1-6 carbon atoms,    -   V is H,H,    -   W is O,    -   B is unsubstituted pyridyl, pyridyl N-oxide, thienyl or        pyrazinyl;

-   in In R¹ is 4-methoxy or 4-ethoxy,    -   R² is 3-methoxy, 3-ethoxy, 3-propoxy, 3-isopropoxy or        3-cyclopentyloxy,    -   X is N,    -   R³ is H or alkyl having 1-6 carbon atoms,    -   V is H,H,    -   W is O,    -   B is unsubstituted pyridyl, pyridyl N-oxide, thienyl or        pyrazinyl or phenyl, which is unsubstituted or may be        monosubstituted by OH, OA, NO₂, NH₂, NAA′,

-   -   A and A′ are each, independently of one another, alkyl having        1-10 carbon atoms, in which 1-7 H atoms may be replaced by F        and/or Cl;        and pharmaceutically usable derivatives, solvates and        stereoisomers thereof, including mixtures thereof in all ratios.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants which are known per se, but arenot mentioned here in greater detail.

In the compounds of the formulae II and III, R¹, R², R³, X and B havethe meanings indicated, in particular the preferred meanings indicated.

Some of the starting materials of the formula II are known. If they arenot known, they can be prepared by methods known per se.

Some of the starting materials of the formula III are known. If they arenot known, they can be prepared by methods known per se.

If desired, the starting materials can also be formed in situ by notisolating them from the reaction mixture, but instead immediatelyconverting them further into the compounds of the formula I. On theother hand, it is possible to carry out the reaction stepwise.

The compounds of the formula I can preferably be obtained by reactingcompounds of the formula II with compounds of the formula III.

In detail, the reaction of the compounds of the formula II with thecompounds of the formula III is carried out in the presence or absenceof an inert solvent at temperatures between approximately −20 andapproximately 150°, preferably between 20 and 100°.

Examples of suitable inert solvents are hydrocarbons such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbonssuch as trichloroethylene, 1,2-dichloroethane, carbon tetra-chloride,chloroform or dichloromethane; alcohols such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers such as ethylene glycol monomethyl ether, ethylene glycolmonoethyl ether (methyl glycol or ethyl glycol), ethylene glycoldimethyl ether (diglyme); ketones such as acetone or butanone; amidessuch as acetamide, dimethylacetamide or dimethylformamide (DMF);nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide(DMSO); carbon disulfide; carboxylic acids such as formic acid or aceticacid; nitro compounds such as nitromethane or nitrobenzene; esters suchas ethyl acetate, or mixtures of the above-mentioned solvents.

In the compounds of the formula III, L is preferably Cl, Br, I or a freeor reactively modified OH group, such as, for example, an activatedester, an imidazolide or alkylsulfonyloxy having 1-6 carbon atoms(preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) orarylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- orp-tolylsulfonyloxy). Radicals of this type for activation of thecarboxyl group in typical acylation reactions are described in theliterature (for example in the standard works, such as Houben-Weyl,Methoden der organischen Chemie [Methods of Organic Chemistry],Georg-Thieme-Verlag, Stuttgart). Activated esters are advantageouslyformed in situ, for example by addition of HOBt or N-hydroxysuccinimide.

Esters can be saponified, for example, using acetic acid or using NaOHor KOH in water, water/THF or water/dioxane, at temperatures between 0and 100°.

Free amino and/or hydroxyl groups can furthermore be acylated in aconventional manner using an acid chloride or anhydride or alkylatedusing an unsubstituted or substituted alkyl halide or reacted withCH₃—C(═NH)— OEt, advantageously in an inert solvent, such asdichloromethane or THF and/or in the presence of a base, such astriethylamine or pyridine, at temperatures between −60 and +30°.

It is furthermore possible to convert a compound of the formula I intoanother compound of the formula I by converting one or more radical(s)R¹, R², R³ and/or B into one or more other radicals R¹, R², R³ and/or B,for example by

-   i) cleaving an ether or ester,-   ii) alkylating or acylating an OH function,-   iii) reductively alkylating an amine by reaction with aldehydes and    complex hydrides,-   iv) reacting an amino group with malononitrile,-   v) reducing a nitro group to an amino group (for example by    hydrogenation on Raney nickel or Pd/carbon in an inert solvent, such    as methanol or ethanol),-   vi) converting a cyano group into a tetrazole group,-   vii) saponifying a carboxyl group by reaction with alcohols, and/or-   viii) alkylating a nitro group under hydrogenolytic conditions,    giving an alkylated amine.    Pharmaceutical Salts and Other Forms

The above-described compounds according to the invention can be used intheir final, non-salt form. On the other hand, the present inventionalso covers the use of these compounds in the form of theirpharmaceutically acceptable salts which can be derived from variousorganic and inorganic acids and bases by procedures well known in theart. Pharmaceutically acceptable salt forms of the compounds of theformula I are prepared for the most part by conventional means. If thecompound of the formula I contains a carboxyl group, a suitable saltthereof can be formed by reacting the compound with a suitable base togive the corresponding base-addition salt. Examples of such bases arealkali metal hydroxides including potassium hydroxide, sodium hydroxide,and lithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. Also included arethe aluminium salts of the compounds of the formula I. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide; other mineral acids andtheir corresponding salts, such as sulfate, nitrate, phosphate, etc.;and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate; and other organic acids and theircorresponding salts, such as acetate, tartrate, maleate, succinate,citrate, benzoate, salicylate, ascorbate, etc. Accordingly, thepharmaceutically acceptable acid-addition salts of the compounds of theformula I include, but are not limited to, the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate and phthalate.

Furthermore, base salts of the compounds according to the inventioninclude, but are not limited to, aluminium, ammonium, calcium, copper,iron(III), iron(II), lithium, magnesium, manganese(III), manganese(II),potassium, sodium and zinc salts. Of the above-mentioned salts,preference is given to ammonium; the alkali metal salts sodium andpotassium, and the alkaline earth metal salts calcium and magnesium.Salts of the compounds of the formula I derived from pharmaceuticallyacceptable organic non-toxic bases include, but are not limited to,salts of primary, secondary and tertiary' amines, substituted amines,including naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris-(hydroxymethyl)methylamine(tromethamine).

Compounds of the present invention which contain basic nitrogen-containing groups may be quaternised using agents such as (C₁-C₄)alkylhalides, for example methyl, ethyl, isopropyl and tert-butyl chlorides,bromides and iodides; di(C₁-C₄)alkyl sulfates, for example dimethyl,diethyl and diamyl sulfates; (C₁₀C₁₈)alkyl halides, for example decyl,dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides;and aryl(C₁-C₄)alkyl halides, for example benzyl chloride and phenethylbromide. Such salts enable the preparation of both water-soluble andoil-soluble compounds according to the invention.

The preferred pharmaceutical salts mentioned above include, but are notlimited to, acetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thlomalate,tosylate and tromethamine.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, giving the salt in a conventional manner. The freebase can be regenerated in a conventional manner by bringing the saltform into contact with a base and isolating the free base. The free baseforms differ to a certain extent from their respective salt forms incertain physical properties, such as solubility in polar solvents;otherwise, however, the salts are equivalent to their respective freebase forms for the purposes of the present invention.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals, or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds of the present invention areprepared by bringing the free acid form into contact with a sufficientamount of the desired base, giving the salt in a conventional manner.The free acid form can be regenerated in a conventional manner bybringing the salt form into contact with an acid and isolating the freeacid form. The free acid forms differ to a certain extent from theirrespective salt forms in physical properties, such as solubility inpolar solvents; otherwise, however, the salts are equivalent to theirrespective free acid forms for the purposes of the present invention.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, invention also covers multiple salts. Examples of typical multiplesalt forms include, but are not limited to, bitartrate, diacetate,difumarate, dimeglumine, diphosphate, disodium and trihydrochloride.

In view of the above, it can be seen that the expression“pharmaceutically acceptable salt” used in the present connection isintended to mean an active ingredient which comprises a compound of theformula I in the form of one of its salts, in particular if this saltform provides the active ingredient with improved pharmacokineticproperties compared with the free form of the active ingredient or anyother salt form of the active ingredient that has been used earlier. Thepharmaceutically acceptable salt form of the active ingredient may alsofor the first time provide the active ingredient with a desirablepharmacokinetic property which it did not previously possess, and mayeven have a positive effect on the pharmacodynamics of this activeingredient with respect to its therapeutic efficacy in the body.

The pharmacokinetic properties of the active ingredient that may befavourably affected include, for example, the manner in which thisactive ingredient is transported through cell membranes, which in turnmay directly and positively affect the absorption, distribution,biotransformation and excretion of this active ingredient. Although themethod of administration of the pharmaceutical composition is important,and various anatomical, physiological and pathological factors cancritically affect bioavailability, the solubility of the activeingredient is usually dependent on the type of the particular salt formthereof which is used. Furthermore, it is clear to the person skilled inthe art that an aqueous solution of the active ingredient ensures thefastest absorption of the active ingredient into the body of a treatedpatient, while lipid solutions and suspensions as well as solid dosageforms result in less rapid absorption of the active ingredient.

Oral ingestion of an active ingredient of the formula I is the mostpreferred method of administration for reasons of safety, convenienceand economy, but absorption of an oral dosage form of this type may beadversely affected by physical properties, such as polarity, vomitingcaused by irritation of the gastrointestinal mucous membrane,degradation by digestive enzymes and low pH, irregular absorption orpropulsion in the presence of foods or other medicaments and metabolismby enzymes of the mucous membrane, the intestinal flora or the liver.Formulation of the active ingredient as different pharmaceuticallyacceptable salt forms may be effective in overcoming or alleviating oneor more of the above-mentioned problems in connection with absorption oforal dosage forms.

A compound of the formula I prepared by the processes described hereincan be separated from the reaction mixture in which it is ultimatelyprepared by any desired conventional method that is familiar to thechemist in the area of organic synthesis. The separated-off compoundscan be purified by known methods. Various methods and techniques can beused for the separation and purification, including, for example,distillation, recrystallisation, column chromatography, ion-exchangechromatography, gel chromatography, affinity chromatography, preparativethin-layer chromatography and solvent extraction.

Stereoisomers

A compound which conforms to the formula I may be of such a nature thatits constituent atoms are capable of being arranged spatially in two ormore ways, despite having identical bonds. As a consequence, thesecompound exists in the form of stereoisomers. Cis/trans isomerism isonly one type of stereoisomerism. If the stereoisomers are image andmirror image which cannot be superimposed, they are enantiomers whichhave chirality or handedness since one or more asymmetric carbon atomsare present in the structure forming them. Enantiomers are opticallyactive and therefore distinguishable since they rotate the plane ofpolarised light to an equal extent, but in opposite directions.

If two or more asymmetric carbon atoms are present in a compound of theformula I, two possible configurations exist at each of these carbonatoms. If two asymmetric carbon atoms are present, four possiblestereoisomers exist, for example. Furthermore, these four possiblestereoisomers can be divided into six possible pairs of stereoisomersthat differ from each other. In order for a pair of molecules with morethan one asymmetric carbon to be enantiomers, they must have differentconfigurations at each asymmetric carbon. Those pairs that are notrelated as enantiomers have a different stereochemical relationship,which is known as a diastereomeric relationship. Stereoisomers that arenot enantiomers are known as diastereoisomers, or, more frequently,diastereomers.

All of these well-known aspects of the stereochemistry of the compoundsof the formula I are considered to be part of the present invention. Thepresent invention therefore covers compounds of the formula I which arestereoisomers, and, if these are enantiomers, the individualenantiomers, racemic mixtures of these enantiomers, and artificial, i.e.synthetic, mixtures comprising proportions of these enantiomers whichare different from the proportions of these enantiomers observed in aracemic mixture. If a compound of the formula I has stereoisomers thatare diastereomers, this compound includes the individual diastereomersas well as mixtures of any two or more of these diastereomers in anydesired proportions.

The following is intended to serve for explanation: if a singleasymmetric carbon atom exists in a compound of the formula I thatresults in the (−)(R) and (+)(S) enantiomers thereof, this compoundincludes all pharmaceutically acceptable salt forms, prodrugs andmetabolites thereof which are therapeutically active and useful fortreating or preventing the diseases and conditions described furtherherein. If a compound of the formula I exists in the form of (−)(R) and(+)(S) enantiomers, this compound also includes the (+)(S) enantiomeralone or the (−)(R) enantiomer alone if all, substantially all or apredominant share of the therapeutic activity resides in only one ofthese enantiomers or undesired side effects reside in only one of theseenantiomers. If essentially no difference exists between the biologicalproperties of the two enantiomers, this compound of the formula Ifurthermore includes the (+)(S) enantiomer and the (−)(R) enantiomertogether as a racemic mixture or non-racemic mixture in any desiredratio of corresponding proportions.

The specific biological activities and/or physical and chemicalproperties of a pair or set of enantiomers of a compound of the formulaI—if present —may make is obvious to use these enantiomers in certainratios to form a final therapeutic product. The following is intended toserve for illustration: if a pair of enantiomers exists, the enantiomerscan be used in ratios of 90% (R)-10% (S), 80% (R)-20% (S), 70% (R)-30%(S), 60% (R)-40% (S), 50% (R)-50% (S), 40% (R)-60% (S), 30% (R)-70% (S),20% (R)-80% (S), and 10% (R)-90% (S). After evaluation of the propertiesof the various enantiomers of a compound of the formula I—if theyexist—the corresponding amount of one or more of these enantiomershaving certain desired properties which form the final therapeuticproduct can be determined in a simple manner.

Isotopes

There is furthermore intended that a compound of the formula I includesisotope-labelled forms thereof. An isotope-labelled form of a compoundof the formula I is identical to this compound apart from the fact thatone or more atoms of the compound have been replaced by an atom or atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the atom which usually occurs naturally. Examples ofisotopes which are readily commercially available and which can beincorporated into a compound of the formula I by well-known methodsinclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,fluorine and chlorine, for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P,³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. A compound of the formula I, aprodrug, thereof or a pharmaceutically acceptable salt of either whichcontains one or more of the above-mentioned isotopes and/or otherisotopes of other atoms is intended to be part of the present invention.An isotope-labelled compound of the formula I can be used in a number ofbeneficial ways. For example, an isotope-labelled compound of theformula I into which, for example, a radioisotope, such as ³H or ¹⁴C,has been incorporated is suitable for medicament and/or substrate tissuedistribution assays. These radioisotopes, i.e. tritium (³H) andcarbon-14 (¹⁴C), are particularly preferred owing to simple preparationand excellent detectability. Incorporation of heavier isotopes, forexample deuterium (²H), into a compound of the formula I has therapeuticadvantages owing to the higher metabolic stability of thisisotope-labelled compound. Higher metabolic stability translatesdirectly into an increased in vivo half-life or lower dosages, whichunder most circumstances would represent a preferred embodiment of thepresent invention. An isotope-labelled compound of the formula I canusually be prepared by carrying out the procedures disclosed in thesynthesis schemes and the related description, in the example part andin the preparation part in the present text, replacing anon-isotope-labelled reactant by a readily available isotope-labelledreactant.

Deuterium (²H) can also be incorporated into a compound of the formula Ifor the purpose in order to manipulate the oxidative metabolism of thecompound by way of the primary kinetic isotope effect. The primarykinetic isotope effect is a change of the rate for a chemical reactionthat results from exchange of isotopic nuclei, which in turn is causedby the change in ground state energies necessary for covalent bondformation after this isotopic exchange. Exchange of a heavier isotopeusually results in a lowering of the ground state energy for a chemicalbond and thus cause a reduction in the rate in rate-limiting bondbreakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexplanation: if deuterium is bonded to a carbon atom at anon-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is successfully applied to a compoundof the formula I that is susceptible to oxidation, the profile of thiscompound in vivo can be drastically modified and result in improvedpharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimise pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the formula I with improved stability throughresistance to such oxidative metabolism. Significant improvements in thepharmacokinetic profiles of compounds of the formula I are therebyobtained, and can be expressed quantitatively in terms of increases inthe in vivo half-life (t/2), concentration at maximum therapeutic effect(C_(max)), area under the dose response curve (AUC), and F; and in termsof reduced clearance, dose and materials costs.

The following is intended to illustrate the above: a compound of theformula I which has multiple potential sites of attack for oxidativemetabolism, for example benzylic hydrogen atoms and hydrogen atomsbonded to a nitrogen atom, is prepared as a series of analogues in whichvarious combinations of hydrogen atoms are replaced by deuterium atoms,so that some, most or all of these hydrogen atoms have been replaced bydeuterium atoms. Half-life determinations enable favourable and accuratedetermination of the extent of the extent to which the improvement inresistance to oxidative metabolism has improved. In this way, it isdetermined that the half-life of the parent compound can be extended byup to 100% as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of the formula I can also beused to achieve a favourable modification of the metabolite spectrum ofthe starting compound in order to diminish or eliminate undesired toxicmetabolites. For example, if a toxic metabolite arises through oxidativecarbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed thatthe deuterated analogue will greatly diminish or eliminate production ofthe unwanted metabolite, even if the particular oxidation is not arate-determining step. Further information on the state of the art withrespect to deuterium-hydrogen exchange may be found, for example inHanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J.Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al.Carcinogenesis 16(4), 683-688, 1993.

Therapeutic Applications

The invention furthermore relates to the use of compounds of the formulaI for treating myocardial diseases.

Coronary heart disease is the most frequent cause of death in theWestern world. If the coronary vessel is critically narrowed, a decreaseof blood flow may result in myocardial ischaemia. Initiation ofreperfusion results, depending on the severity of the precedingischaemic period, in a reversibly or irreversibly damaged myocardium,which is characterised by long-lasting depression or an irreversibleloss of contractile function. Depending on the size of the affectedmyocardial area, acute or a chronic heart failure may develop.

A particular clinical problem in the above mentioned case is thedevelopment of restenosis after initially successful reperfusion byPTCA, even after stent implantation, after thrombolysis or aftertransplant of an aortocoronary bypass. From experimental animal studiesand clinical studies, there is evidence that inflammatory processes playa casual role in the various heart diseases mentioned above, i.e.coronary heart disease itself, reversible or irreversible myocardialischemia/reperfusion damage, acute or chronic heart failure andrestenosis, including in-stent restenosis and stent-in-stent restenosis.These inflammatory processes involve resident and invading macrophagesas well as neutrophils and TH₁ and TH₂ helper cells. This leukocyteresponse produces the characteristic cytokine pattern involving TNF-α,IL-1β, IL-2 and IL-6, as well as IL-10 and IL-13 (Pulkki K J: Cytokinesand cardiomyocyte death. Ann.Med. 1997 29: 339-343.

Birks E J, Yacoub M H: The role of nitric oxide and cytokines in heartfailure. Coron.Artery.Dis. 1997 8: 389-402).

The formation of these species has been demonstrated in human patientswith myocardial ischemia. Animal models show that cytokine productioncorrelates with the invasion of peripheral macrophages and neutrophils,enabling the damage to spread into the still intact myocardium.

The main factor in the cytokine response, however, is TNF-α, whichcombines inflammatory and pro-apoptotic responses and additionally has adirect negative ionotropic effect on cardiac myocytes (Ceconi C, CurelloS, Bachetti T, Corti A, Ferrari R: Tumor necrosis factor in congestiveheart failure: a mechanism of disease for the new millennium? Prog.Cardiovasc. Dis. 1998 41: 25-30.

Mann D L: The effect of tumor necrosis factor-alpha on cardiac structureand function: a tale of two cytokines. J. Card. Fail. 1996 2: S165-S172.

Squadrito F, Altavilla D, Zingarelli B, et al: Tumor necrosis factorinvolvement in myocardial ischaemia-reperfusion damage. Eur. J.Pharmacol. 1993 237: 223-230).

It has been shown in animal models of myocardial infarction that TNF-αis released rapidly during the reperfusion phase (Herskowitz A, Choi S,Ansari AA, Wesselingh S: Cytokine mRNA expression inpostischemic/reperfused myocardium. Am. J. Pathol. 1995 146: 419-428)and that the protective effects of medicaments, such as dexamethasone(Arras M, Strasser R, Mohri M, et al: Tumor necrosis factor-alpha isexpressed by monocytes/macrophages following cardiac microembolisationand is antagonised by cyclosporine. Basic. Res. Cardiol. 1998 93:97-107), cyclosporin A (Arras M, Strasser R, Mohri M, et al: Tumornecrosis factoralpha is expressed by monocytes/macrophages followingcardiac microembolisation and is antagonised by cyclosporine. Basic.Res. Cardiol. 1998 93: 97-107. Squadrito F, Altavilla D, Squadrito G, etal: Cyclosporin-A reduces leukocyte accumulation and protects againstmyocardial ischaemia reperfusion damage in rats. Eur. J. Pharmacol. 1999364: 159-168) or clorichromene (Squadrito F, Altavilla D, Zingarelli B,et al: The effect of cloricromene, a coumarine derivative, on leukocyteaccumulation, myocardial necrosis and TNF-alpha production in myocardialischaemia-reperfusion damage. Life Sci. 1993 53: 341-355) areaccompanied by a reduction of circulating TNF-α.

PDE IV inhibitors of the formula I are potent antagonists of macrophageand T-cell cytokine production. They also inhibit the proliferation of Tcells. PDE IV inhibition may therefore have a beneficial effect inmyocardial diseases which are causally linked to cytokine production andinflammatory processes.

Compared with PDE III inhibitors and the earlier PDE IV inhibitorrolipram, preferred PDE IV inhibitors have no haemodynamic side effects,which can result in a restriction of the dose in the treatment of mostcardiovascular disorders.

The invention had the object of finding novel potential uses ofcompounds having valuable properties, especially those which can be usedfor the preparation of medicaments.

It has been found that the compounds of the formula I and their saltsboth have extremely valuable pharmacological properties and are welltolerated in the treatment of myocardial diseases.

The invention preferably proposes the use of the compounds of theformula I for the preparation of a medicament for the treatment ofmyocardial diseases, where these myocardial diseases have inflammatoryand immunological features.

The invention most preferably proposes the use of the compounds of theformula I for the preparation of a medicament for the treatment ofcoronary heart disease, reversible or irreversible myocardialischemia/reperfusion damage, acute or chronic heart failure andrestenosis, including instent restenosis and stent-in-stent restenosis.

The invention preferably proposes the use of the compounds of theformula I for the preparation of a medicament for the treatment orprevention of one or more of the following diseases, pathologicaldisorders or conditions from the group consisting of:

-   -   asthma of whatever type, etiology or pathogenesis, or asthma        selected from the group consisting of atopic asthma, non-atopic        asthma, allergic asthma, atopic, bronchial, IgE-mediated asthma,        bronchial asthma, essential asthma, true asthma, intrinsic        asthma caused by pathophysiological disturbances, extrinsic        asthma caused by environmental factors, essential asthma of        unknown or inapparent cause, non-atopic asthma, bronchitic        asthma, emphysematous asthma, exercise-induced asthma,        occupational asthma, infective asthma caused by bacterial,        fungal, protozoal, or viral infection, non-allergic asthma,        incipient asthma and wheezy infant syndrome;    -   chronic or acute bronchoconstriction, chronic bronchitis, small        airway obstruction and emphysema;    -   obstructive or inflammatory airway diseases of whatever type,        etiology or pathogenesis, or an obstructive or inflammatory        airway disease selected from the group consisting of asthma,        pneumoconiosis, chronic eosinophilic pneumonia, chronic        obstructive pulmonary disease (COPD), COPD including chronic        bronchitis, pulmonary emphysema or dyspnea associated therewith,        COPD that is characterised by irreversible, progressive airway        obstruction, adult respiratory distress syndrome (ARDS), and        exacerbation of airway hyper-reactivity consequent to other        medicament therapy;    -   pneumoconiosis of whatever type, etiology or pathogenesis, or        pneumoconiosis selected from the group consisting of aluminosis        or bauxite workers' disease, anthracosis or miners' asthma,        asbestosis or steam-fitters' asthma, chalicosis or flint        disease, ptilosis caused by inhaling the dust from ostrich        feathers, siderosis caused by the inhalation of iron particles,        silicosis or grinders' disease, byssinosis or cotton-dust asthma        and talc pneumoconiosis;    -   bronchitis of whatever type, etiology or pathogenesis, or        bronchitis selected from the group consisting of acute        bronchitis, acute laryngotracheal bronchitis, arachidic        bronchitis, catarrhal bronchitis, croupus bronchitis, dry        bronchitis, infectious asthmatic bronchitis, productive        bronchitis, staphylococcus or streptococcal bronchitis and        vesicular bronchitis;    -   bronchiectasis of whatever type, etiology or pathogenesis, or        bronchiectasis selected from the group consisting of cylindric        bronchiectasis, sacculated bronchiectasis, fusiform        bronchiectasis, capillary bronchiectasis, cystic bronchiectasis,        dry bronchiectasis and follicular bronchiectasis;    -   seasonal allergic rhinitis, or perennial allergic rhinitis, or        sinusitis of whatever type, etiology or pathogenesis, or        sinuisitis selected from the group consisting of purulent or        nonpurulent sinusitis, acute or chronic sinusitis and ethmoid,        frontal, maxillary, or sphenoid sinusitis;    -   rheumatoid arthritis of whatever type, etiology or pathogenesis,        or rheumatoid arthritis selected from the group consisting of        acute arthritis, acute gouty arthritis, chronic inflammatory        arthritis, degenerative arthritis, infectious arthritis, Lyme        arthritis, proliferative arthritis, psoriatic arthritis and        vertebral arthritis;    -   gout, and fever and pain associated with inflammation;    -   an eosinophil-related pathological disorder of whatever type,        etiology or pathogenesis, or an eosinophil-related pathological        disorder selected from the group consisting of eosinophilia,        pulmonary infiltration eosinophilia, Loffier's syndrome, chronic        eosinophilic pneumonia, tropical pulmonary eosinophilia,        bronchopneumonic aspergillosis, aspergilloma, granulomas        containing eosinophils, allergic granulornatous angijtis or        Churg-Strauss syndrome, polyarteritis nodosa (PAN) and systemic        necrotising vasculitis;    -   atopic dermatitis, allergic dermatitis or allergic or atopic        eczema;    -   urticaria of whatever type, etiology or pathogenesis, or        urticaria selected from the group consisting of immune-mediated        urticaria, complement-mediated urticaria, urticariogenic        material-induced urticaria, physical stimulus-induced urticaria,        stressinduced urticaria, idiopathic urticaria, acute urticaria,        chronic urticaria, angioedema, cholinergic urticaria, cold        urticaria in the autosomal dominant form or in the acquired        form, contact urticaria, giant urticaria and papular urticaria;    -   conjunctivitis of whatever type, etiology or pathogenesis, or        conjunctivitis selected from the group consisting of actinic        conjunctivitis, acute catarrhal conjunctivitis, acute contagious        conjunctivitis, allergic conjunctivitis, atopic conjunctivitis,        chronic catarrhal conjunctivitis, purulent conjunctivitis and        vernal conjunctivitis;    -   uveitis of whatever type, etiology or pathogenesis, or uveitis        selected from the group consisting of inflammation of all or        part of the uvea, anterior uveitis, iritis, cyclitis,        iridocyclitis, granulornatous uveitis, nongranulornatous        uveitis, phacoantigenic uveitis, posterior uveitis, choroiditis        and chorioretinitis;    -   psoriasis;    -   multiple sclerosis of whatever type, etiology or pathogenesis,        or multiple sclerosis selected from the group consisting of        primary progressive multiple sclerosis and relapsing remitting        multiple sclerosis;    -   autoimmune/inflammatory diseases of whatever type, etiology or        pathogenesis, or an autoimmune/inflammatory disease selected        from the group consisting of autoimmune hematological disorders,        hemolytic anaemia, aplastic anaemia, pure red cell anaemia,        idiopathic thrombocytopenic purpura, systemic lupus        erythematosus, polychondritis, sclerorma, Wegner's        granulomatosis, dermatomyositis, chronic active hepatitis,        myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue,        autoimmune inflammatory bowel diseases, ulcerative colitis,        Crohn's disease, endocrin opthamopathy, Grave's disease,        sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis,        primary biliary cirrhosis, juvenile diabetes or diabetes        mellitus type 1, anterior uveitis, granulornatous or posterior        uveitis, keratoconjunctivitis sicca, epidemic        keratoconjunctivitis, diffuse interstitial pulmonary fibrosis or        interstitial lung fibrosis, idiopathic pulmonary fibrosis,        cystic fibrosis, psoriatic arthritis, glomerulonephritis with        and without nephrotic syndrome, acute glomerulonephritis,        idiopathic nephrotic syndrome, minimal change nephropathy,        inflammatory/hyperproliferative skin diseases, psoriasis, atopic        dermatitis, contact dermatitis, allergic contact dermatitis,        benign familial pemphigus, pemphigus erythematosus, pemphigus        foliaceus and pemphigus vulgaris;    -   prevention of foreign trasnplant rejection following organ        transplantation;    -   inflammatory bowel disease (IBD) of whatever type, etiology or        pathogenesis, or inflammatory bowel disease selected from the        group consisting of ulcerative colitis (UC), collagenous        colitis, colitis polyposa, transmural colitis and Crohn's        disease (CD);    -   septic shock of whatever type, etiology or pathogenesis, or        septic shock selected from the group consisting of renal        failure, acute renal failure, cachexia, malarial cachexia,        hypophysial cachexia, uremic cachexia, cardiac cachexia,        cachexia suprarenalis or Addison's disease, cancerous cachexia,        and cachexia as a consequence of infection by the human        immunodeficiency virus (HIV);    -   liver damage;    -   pulmonary hypertension and hypoxia-induced pulmonary        hypertension;    -   bone loss diseases, primary osteoporosis and secondary        osteoporosis;    -   pathological disorders of the central nervous system of whatever        type, etiology or pathogenesis, or a pathological disorder of        the central nervous system selected from the group consisting of        depression, Parkinson's disease, learning and memory impairment,        tardive dyskinesia, drug dependence, arteriosclerotic dementia,        and dementias that accompany Huntington's chorea, Wilson's        disease, paralysis agitans and thalamic atrophies;    -   infections, especially viral infections, where these viruses        increase the production of TNF-α in their host and where these        viruses are sensitive to up-regulation of TNF-α in their host so        that their replication or other vital activities are adversely        affected, including viruses selected from the group consisting        of HIV-1, HIV-2 and HIV-3, cytornegalovirus, CMV, influenza,        adenoviruses and Herpes viruses, including Herpes zoster and        Herpes simplex;    -   yeast and fungus infections, where these yeasts and fungi are        sensitive to up-regulation by TNF-α or elicit TNF-α production        in their host, for example fungal meningitis, particularly when        administered in conjunction with other medicaments of choice for        the treatment of systemic yeast and fungus infections,        including, but are not limited to, polymycins, for example        polymycin B, imidazoles, for example clotrimazole, econazole,        miconazole and ketoconazole, triazoles, for example fluconazole        and itranazole and amphotericins, for example amphotericin B and        liposomal amphotericin B;    -   ischemia-reperfusion damage, autoimmune diabetes, retinal        autoimmunity, chronic lymphocytic leukemia, HIV infections,        lupus erythematosus, kidney and ureter disease, urogenital and        gastrointestinal disorders and prostate diseases.

In particular, compounds of the formula I are suitable for the treatmentof (1) inflammatory diseases and conditions, including jointinflammation, rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, inflammatory bowel disease, ulcerative colitis, chronicglomerulonephritis, dermatitis and Crohn's disease, (2) respiratorytract diseases and conditions, including asthma, acute respiratorydistress syndrome, chronic pulmonary inflammatory disease, bronchitis,chronic obstructive airway disease and silicosis, (3) infectiousdiseases and conditions, including sepsis, septic shock, endotoxicshock, Gram-negative sepsis, toxic shock syndrome, fever and myalgiasdue to bacterial, viral or fungal infection, and influenza, (4) immunediseases and conditions, including autoimmune diabetes, systemic lupuserythematosis, GvH reaction, rejection of foreign transplants, multiplesclerosis, psoriasis and allergic rhinitis, and (5) other diseases andconditions, including bone absorption diseases, reperfusion damage,cachexia secondary to infection or malignancy, cachexia secondary tohuman acquired immune deficiency syndrome (AIDS), human immunodeficiencyvirus (HIV) infection, or AIDS related complex (ARC), keloid formation,scar tissue formation, type 1 diabetes mellitus and leukaemia.

The present invention further relates to the combination of a compoundof the formula I together with one or more members selected from thegroup consisting of the following:

-   (a) leukotriene biosynthesis inhibitors: 5-lipoxygenase (5-LO)    inhibitors and 5-lipoxygenase activating protein (FLAP) antagonists    selected from the group consisting of zileuton, ABT-761, fenleuton,    tepoxalin, Abbott-79175, Abbott-85761,    N-(5-substituted)-thiophene-2-alkylsulfonamides,    2,6-di-tert-butylphenol hydrazones, the class of the    methoxytetrahydropyrans, including Zeneca ZD-2138, the compound    SB-210661 and the class to which it belongs, the class of the    pyridinyl-substituted 2-cyanonaphthalene compounds, including L    739,010, the class of the 2-cyanoquinoline compounds, including    L-746,530, the classes of the indole and quinoline compounds,    including MK-591, MK-886 and BAY x 1005; (b) receptor antagonists    for the leukotrienes LTB₄, LTC₄, LTD₄ and LTE₄ selected from the    group consisting of the class of the phenothiazin-3-one compounds,    including L-651,392, the class of the amidino compounds, including    CGS-25019c, the class of the benzoxaolamines, including ontazolast,    the class of the benzenecarboximidamides, including BIIL 284/260,    and the classes of compound to which zafirlukast, ablukast,    montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913,    iralukast (CGP 45715A) and BAY x 7195 belong; (c) PDE IV    inhibitors; (d) 5-lipoxygenase (5-LO) inhibitors; or 5-lipoxygenase    activating protein (FLAP) antagonists; (e) dual inhibitors of    5-lipoxygenase (5-LO) and antagonists of platelet activating factor    (PAF); (f) leukotriene antagonists (LTRAs) including LTB₄, LTC₄,    LTD₄ and LTE₄ antagonists; (g) antihistamine H, receptor    antagonists, including cetirizine, loratadine, desioratadine,    fexofenadine, astemizole, azelastine and chlorpheniramine; (h)    gastroprotective H₂ receptor antagonists; (i) α₁- and    α₂-adrenoceptor agonist vasoconstrictor sympathomimetic agents    administered orally or topically for decongestant use, including    propylhexedrine, phenylephrine, phenylpropanolamine,    pseudoephedrine, naphazoline hydrochloride, oxymetazoline    hydrochloride, tetrahydrozoline hydrochloride, xylometazoline    hydrochloride and ethyinorepinephrine hydrochloride; j) α₁- and    α₂-adrenoceptor agonists in combination with inhibitors of    5-lipoxygenase (5-LO); (k) anticholinergic agents, including    ipratropium bromide, tiotropiurn bromide, oxitropium bromide,    pirenzepine and telenzepine; (I) β₁- to β₄-adrenoceptor agonists,    including metaproterenol, isoproterenol, isoprenaline, albuterol,    salbutamol, formoterol, salmeterol, terbutaline, orciprenaline,    bitolterol mesylate and pirbuterol; (m) methylxanthanines, including    theophylline and aminophylline; (n) sodium cromoglycate; (o)    muscarinic receptor (M1, M2 and M3) antagonists; (p) COX-1    inhibitors (NSAIDs); COX-2 selective inhibitors, including    rofecoxib, and nitric oxide NSAIDs; (q) insulin-like growth factor    type I (IGF-1) mimetics; (r) ciclesonide; (s) inhalation    glucocorticoids with reduced systemic side effects, including    prednisone, prednisolone, flunisolide, triamcinolone acetonide,    beclomethasone dipropionate, budesonide, fluticasone propionate and    mometasone furoate; (t) tryptase inhibitors; (u) platelet activating    factor (PAF) antagonists; (v) monoclonal antibodies against    endogenous inflammatory entities; (w) IPL 576; (x) antitumour    necrosis factor (TNFα) agents, including etanercept, infliximab and    D2E7; (y) DMARDs, including leflunomide; (z) TCR peptides; (aa)    interleukin converting enzyme (ICE) inhibitors; (bb) IMPDH    inhibitors; (cc) adhesion molecule inhibitors, including VLA-4    antagonists; (dd) cathepsins; (ee) MAP kinase inhibitors; (ff)    glucose 6-phosphate dehydrogenase inhibitors; (gg) kinin B₁ and B₂    receptor antagonists; (hh) gold in the form of an aurothio group    together with various hydrophilic groups; (ii) immunosuppressive    agents, for example cyclosporine, azathioprine and methotrexate;    (jj) antigout agents, for example colchicine; (kk) xanthine oxidase    inhibitors, for example allopurinol; (ll) uricosuric agents, for    example probenecid, sulfinpyrazone and benzbromarone; (mm)    antineoplastic agents, especially antimitotic medicaments, including    the vinca alkaloids, such as vinblastine and vincristine; (nn)    agents which promote growth hormone secretion; (oo) inhibitors of    matrix metalloproteases (MMPs), i.e. the stromelysins, collagenases    and gelatinases, as well as aggrecanase, especially collagenase-1    (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13),    stromelysin-1 (MMP-3), stromelysin-2 (MMP-10) and stromelysin-3    (MMP-11); (pp) transforming growth factor (TGFβ); (qq)    platelet-derived growth factor (PDGF); (rr) fibroblast growth    factor, for example basic fibroblast growth factor (bFGF); (ss)    granulocyte macrophage colony stimulating factor (GM-CSF); (tt)    capsaicin; (uu) tachykinin NK₁ and NK₃ receptor antagonists selected    from the group consisting of NKP-608C, SB233412 (talnetant) and    D4418; and (vv) elastase inhibitors selected from the group    consisting of UT-77 and ZD-0892.

The present invention relates to a combination of a compound of theformula I together with one or more additional therapeutic agents forjoint administration to a patient in order to obtain a particularlydesired therapeutic end result. The second, etc. therapeutic agent maylikewise be one or more compounds as described above or one or more PDEIV inhibitors known in this art and described in greater detail here. Inparticular, the second, etc. therapeutic agent is selected from adifferent class of therapeutic agents. These selected combinations aredescribed in greater detail below.

In the present connection, the terms “joint administration”, “jointlyadministered” and “in combination with”, if they refer to the compoundsof the formula I and one or more other therapeutic agents, is taken tomean and does refer to and include the following:

-   (a) simultaneous administration of a combination of this type of    compound(s) and therapeutic agent(s) to a patient in need of    treatment if these components are formulated jointly as a single    dosage form which releases these components to the patients at    essentially the same time;-   (b) essentially simultaneous administration of a combination of this    type of compound(s) and therapeutic agent(s) to a patient in need of    treatment if these components are formulated separately as separate    dosage forms which are taken by patient at essentially the same    time, and the components are released to these patients at    essentially the same time;-   (c) sequential administration of a combination of this type of    compound(s) and therapeutic agent(s) to a patient in need of    treatment if these components are formulated separately from one    another as separate dosage forms which are taken by the patient at    successive times with a clear time interval between each taking, and    the components are released to the patients at essentially different    times; and-   (d) sequential administration of a combination of this type of    compound(s) and therapeutic agent(s) to a patient in need of    treatment if these components are formulated jointly as a single    dosage form which releases these components in a controlled manner,    and the components are taken by the patient simultaneously,    successively and/or overlappingly at the same time and/or at    different times.

Combinations with Leukotriene Biosynthesis Inhibitors: 5-lipoxygenase(5-LO) Inhibitors and 5-lipoxygenase Activating Protein (FLAP)Antagonists

In order to form embodiments according to the invention, one or more ofthe compounds of the formula I is (are) used in combination withleukotriene biosynthesis inhibitors, i.e. 5-lipoxygenase inhibitors or5-lipoxygenase activating protein antagonists. 5-Lipoxygenase (5-LO) isone of two groups of enzymes which metabolise arachidonic acid, theother group being the cyclooxygenases, COX-1 and COX-2.

5-lipoxygenase activating protein is an membrane-bound,arachidonate-binding protein with a size of 18 kDa which stimulates theconversion of arachidonic acid in the cell by 5-lipoxygenase. Thearachidonic acid is converted into 5-hydroperoxyeicosatetraenoic acid(5-HPETE), and this route ultimately leads to the production ofinflammatory leukotrienes; blocking of 5-lipoxygenase activating proteinor the enzyme 5-lipoxygenase itself therefore represents a desirable aimfor favourably influencing this route. One of these 5-lipoxygenaseinhibitors is zileuton.

The classes of leukotriene synthesis inhibitors which are suitable forthe formation of therapeutic combinations with the compounds of theformula I include the following:

-   (a) redox-active agents, including N-hydroxyureas, N-alkylhydroxamid    acids, selenite, hydroxybenzofurans, hydroxylamines and catechols,    see Ford-Hutquinson et al, “5-Lipoxygenase,”, Ann. Rev. Biochem. 63,    383-417,1994; Weitzel and Wendel, “Selenoenzymes regulate the    activity of leukocyte 5-lipoxygenase via the peroxide tone”, J.    Biol. Chem. 268, 6288-92, 1993; Björnstedt et al. “Selenite    incubated with NADPH and mammalian thioredoxin reductase yields    selenide, which inhibits lipoxygenase and changes the electron spin    resonance spectrum of the active site iron”, Biochemistry 35,    8511-6, 1996; and Stewart et al., “Structure-activity relationships    of N-hydroxyurea 5-lipoxygenase inhibitors”, J. Med. Chem. 40,    1955-68, 1997;-   (b) alkylating agents and compounds which react with SH groups have    been found to inhibit leukotriene synthesis in vitro; see Larsson et    al., “Effects of 1-chloro-2,4,6-trinitrobenzene on 5-lipoxygenase    activity and cellular leukotriene synthesis”, Biochem. Pharmacol.    55, 863-71, 1998; and-   (c) competitive inhibitors of 5-lipoxygenase based on    thiopyranoindole and methoxyalkyl thiazole structures which act as    non-redox inhibitors of 5-lipoxygenase; see Ford-Hutquinson et al.,    Ibid.; and Hamel et al., “Substituted (pyridylmethoxy)naphthalenes    as potent and orally active 5-lipoxygenase inhibitors - synthesis,    biological profile and pharmacokinetics of L-739,01 0”, J. Med.    Chem. 40, 2866-75, 1997.

The observation that arachidononic acid hydroxyamate inhibits5-lipoxygenase has led to the discovery of clinically useful selective5-lipoxygenase inhibitors, such as the N-hydroxyurea derivativeszileuton and ABT-761, which are shown below:

Another N-hydroxyurea compound is fenleuton (Abbott-76745):

Another N-hydroxyurea compound is Abbott-79175.

Abbott-79175 has a longer duration of action than zileuton; Brooks etal, J. Pharm. Exp. Therapeut 272 724, 1995.

Yet another N-hydroxyurea compound is Abbott-85761

Abbott-85761 is delivered to the lung by aerosol administration of ahomogeneous, physically stable and virtually monodisperse formulation;Gupta et al., “Pulmonary delivery of the 5-lipoxygenase inhibitor,Abbott- 85761, in beagle dogs”, International Journal of Pharmaceutics147, 207-218, 1997.

For the formation of embodiments according to the invention, fenleuton,Abbott-79175, Abbott-85761 or any of the above-described derivativesthereof or tepoxalin derivatives are combined with the compounds of theformula I.

Since the elucidation of the 5-LO biosynthetic pathway, there has beenan ongoing debate as to whether it is more advantageous to inhibit the5-lipoxygenase enzyme or to use antagonists for the peptido- ornon-peptidoleukotriene receptors. Inhibitors of 5-lipoxygenase arethought to be superior to LT receptor antagonists, since 5-lipoxygenaseinhibitors block the action of the entire range of 5-LO products,whereas the action of LT antagonists is narrower. Nevertheless,embodiments according to the invention include combinations of thecompounds of the formula I not only with 5-LO inhibitors, but also withLT antagonists, as described below. Inhibitors of 5-lipoxygenase havingchemical structures which differ from the classes of N-hydroxyureas andhydroxamic acids described above are likewise combined with thecompounds of the formula I and thus form further embodiments accordingto the invention. An example of a different class of this type comprisesthe N-(5-substituted)-thiophene-2-alkylsulfonamides of the followingformula

in which X is O or S; R′ is methyl, isopropyl, n-butyl, n-octyl orphenyl, and R is n-pentyl, cyclohexyl, phenyl, tetrahydro-1-naphthyl, 1-or 2-naphthyl, or phenyl which is monosubstituted or disubstituted byCl, F, Br, CH₃, OCH₃, SCH₃, SO₂CH₃, CF₃, or isopropyl. A preferredcompound is

A more precise description of these compounds is found in Beers et al.,“N-(5-substituted) thiophene-2-alkylsulfonamides as potent inhibitors of5-lipoxygenase”, Bioorganic & Medicinal Chemistry 5(4), 779-786, 1997.

Another different class of 5-lipoxygenase inhibitors is the class of the2,6-di-tert-butylphenol hydrazones which is described in Cuadro et al.,“Synthesis and biological evaluation of 2,6-di-tert.-butylphenolhydrazones as 5-lipoxygenase inhibitors”, Bioorganic & MedicinalChemistry 6, 173-180, 1998. Compounds of this type conform to theformula

in which “Het” is benzoxazol-2-yl, benzothiazol-2-yl, pyridin-2-yl,pyrazin-2-yl, pyrimidin-2-yl, 4-phenylpyrimidin-2-yl,4,6-diphenylpyrimidin-2-yl, 4-methylpyrimidin-2-yl,4,6-dimethylpyrimidin-2-yl, 4-butylpyrimidin-2-yl,4,6-dibutylpyrimidin-2-yl and 4-methyl-6-phenylpyrimidin-2-yl.

The N-(5-substituted)-thiophene-2-alkylsulfonamides or the2,6-di-tert-butylphenol hydrazones or any of the above-describedderivatives thereof are combined with the compounds of the formula Imentioned above and thus form embodiments according to the invention.

A further different class of 5-lipoxygenase inhibitors is that ofmethoxytetrahydropyrans to which Zeneca ZD-2138 belongs

ZD-2138 is highly selective and highly active on oral administration invarious species and has been evaluated in the treatment of asthma andrheumatoid arthritis by oral administration. Further details concerningZD-2138 and derivatives thereof are given in Crawley et al., J. Med.Chem., 35, 2600, 1992, and Crawley et al., J. Med. Chem. 36, 295, 1993.

Another different class of 5-lipoxygenase inhibitors is that comprisingthe SmithKline Beecham compound SB-210661

Two further different, related classes of 5-lipoxygenase inhibitorscomprise various pyridinyl-substituted 2-cyanonaphthalene compounds andvarious 2-cyanoquinoline compounds which were discovered by MerckFrosst. These two classes of 5-lipoxygenase inhibitors are illustratedby L-739,010 and L-746,530, respectively:

Further details concerning L-739,010 and L-746,530 are given in Dubé etal., “Quinolines as potent 5-lipoxygenase inhibitors: synthesis andbiological profile of L-746,530”, Bioorganic & Medicinal Chemistry8,1255-1260, 1998, and in WO 95/03309 (Friesen et al.).

The class of the methoxytetrahydropyrans, including Zeneca ZD-2138, orthe lead compound SB-210661 and the class to which it belongs, or theseries of pyridinyl-substituted 2-cyanonaphthalene compounds, includingL 739,010, or the series of 2-cyanoquinoline compounds, includingL-746,530, or any of the above-described derivatives of any of theabove-mentioned classes, are combined with the compounds of the formulaI and thus form embodiments according to the invention.

The other endogenous substance which, besides the 5-lipoxygenase enzyme,plays a significant role in leukotriene biosynthesis is 5-lipoxygenaseactivating protein (FLAP). in contrast to the direct role of the enzyme5-lipoxygenase, this protein has an indirect role. Nevertheless,antagonists of 5-lipoxygenase activating protein are used to inhibitleukotriene synthesis in the cell and as such they are also used incombination with the compounds of the formula I and thus formembodiments according to the invention.

Compounds which bind to 5-lipoxygenase activating protein and thus blockutilisation of the endogenous pool of arachidonic acid which is presenthave been synthesised from indole and quinoline structures; seeFord-Hutquinson et al., Ibid., Rouzer et al. “WK-886, a potent andspecific leukotriene biosynthesis inhibitor blocks and reverses themembrane association of 5-lipoxygenase in ionophore-challengedleukocytes”, J. Biol. Chem. 265, 1436- 42, 1990, and Gorenne et al.,“{(R)-2-quinolin-2-yl-methoxy)phenyl)-2-cyclopentyl acetic acid} (BAY x1005), a potent leukotriene synthesis inhibitor: effects on anti-IgEchallenge in human airways”, J. Pharmacol. Exp. Ther. 268, 868-72, 1994.

MK-591, with the name quiflipon sodium, conforms to the formula

The above-mentioned indole and quinoline classes of compounds, includingthe specific compounds MK-591, IVIK-886 and BAY x 1005, or any of theabove-described derivatives of any of the above-mentioned classes, arecombined with the compounds of the formula I and thus form embodimentsaccording to the invention.

Combinations with Receptor Antagonists for the Leukotrienes LTB₄, LTC₄,LTD₄ and LTE₄

A compound of the formula I or a plurality of compounds of the formula Iis or are used in combination with receptor antagonists for theleukotrienes LTB₄, LTC₄, LTD₄ and LTE₄. The most significant of theseleukotrienes in terms of mediating an inflammatory response are LTB₄ andLTD₄. Classes of antagonists for the receptors of these leukotrienes aredescribed in the paragraphs which follow.

4-Bromo-2,7-dimethoxy-3H-phenothiazin-3-ones, including L-651,392, arepotent receptor antagonists for LTB₄ which are described in U.S. Pat.No. 4,939,145 (Guindon et al.) and U.S. Pat. No. 4,845,083 (Lau et al.)

A class of amidino compounds, which includes CGS-25019c, is described inU.S. Pat. No. 5,451,700 (Morrissey and Suh); U.S. Pat. No. 5,488,160(Morrissey), and U.S. Pat. No. 5,639,768 (Morrissey and Suh). A typicalrepresentative of these LTB₄ antagonists is CGS-25019c, which is shownbelow:

Ontazolast, a member of a class of benzoxaolamines which are LTB₄antagonists, is described in EP 535 521 (Anderskewitz et al.):

The same group of workers also discovered a class ofbenzenecarboximideamides which are LTB₄ antagonists, which are describedin WO 97/21670 (Anderskewitz et al.) and WO 98/11119 (Anderskewitz etl.) and of which BIIL 284/260 is a typical representative:

Zafirlukast is an LTC₄, LTD₄ and LTE₄ receptor antagonist which iscommercially available under the name Accolate®. It belongs to a classof heterocyclic amide derivatives which is described in U.S. Pat. No.4,859,692 (Bernstein et al.), U.S. Pat. No. 5,319,097 (Holohan andEdwards), U.S. Pat. No. 5,294,636 (Edwards and Sherwood), U.S. Pat. Nos.5,482,963, 5,583,152 (Bernstein et al.), and U.S. Pat. No. 5,612,367(Timko et al.):

Ablukast is an LTD₄ receptor antagonist which carries the designation Ro23-3544/001:

Montelukast is a LTD₄ receptor antagonist which is commerciallyavailable under the name Singulair® and is described in U.S. Pat. No.5,565,473:

Other LTD₄ receptor antagonists include pranlukast, verlukast (MK-679),RG-12525, Ro-245913, iralukast (CGP 45715A) and BAY x 7195.

The above-mentioned phenothiazin-3-one class of compounds, includingL-651,392, the class of amidino compounds including CGS-25019c, theclass of benzoxaolamines which includes ontazolast, the class ofbenzenecarboximidamides which is typified by BIIL 284/260, theheterocyclic amide derivatives including zafirlukast, ablukast andmontelukast and the classes of compounds to which they belong, or any ofthe above-described derivatives of any of the above-mentioned classes,are combined with the compounds of the formula I and thus formembodiments according to the invention.

Combinations with Other Therapeutic Agents

One or more compounds of the formula I are used together with othertherapeutic agents as well as non-therapeutic agents and combinationsare thus formed which are further embodiments according to the inventionand which are suitable for the treatment of a whole series of differentdiseases, pathological disorders and conditions described herein. Theseembodiments include one or more compounds of the formula I together withone or more of the following substances:

-   (a) PDE IV inhibitors;-   (b) 5-lipoxygenase (5-LO) inhibitors or antagonists of    5-lipoxygenase activating protein (FLAP);-   (c) dual inhibitors of 5-lipoxygenase (5-LO) or antagonists of    platelet activating factor (PAF);-   (d) leukotriene antagonists (LTRAs), including LTB₄, LTC₄, LTD₄ and    LTE₄ antagonists;-   (e) antihistamine H₁ receptor antagonists, including cetirizine,    loratadine, desloratadine, fexofenadine, astemizole, azelastine and    chlorpheniramine;-   (f) gastroprotective H₂ receptor antagonists;-   (g) α₁- and α₂-adrenoceptor agonist vasoconstrictor sympathomimetic    agents administered orally or topically for decongestant use,    including propylhexedrine, phenylephrine, phenylpropanolamine,    pseudoephedrine, naphazoline hydrochloride, oxymetazoline    hydrochloride, tetrahydrozoline hydrochloride, xylometazoline    hydrochloride and methylnorepinephrine hydrochloride;-   (h) α₁- and α₂-adrenoceptor agonists in combination with inhibitors    of 5-lipoxygenase (5-LO);-   (i) anticholinergic agents including ipratropium bromide, tiotropium    bromide, oxitropium bromide, pirenzepine and telenzepine;-   (j) β₁- to β₄-adrenoceptor agonists, including metaproterenol,    isoproterenol, isoprenaline, albuterol, salbutamol, formoterol,    salmeterol, terbutaline, orciprenaline, bitolterol mesylate and    pirbuterol;-   (k) theophylline and aminophylline;-   (l) sodium cromoglycate;-   (m) muscarinic receptor (M1, M2 and M3) antagonists;-   (n) COX-1 inhibitors (NSAIDs); COX-2 selective inhibitors, including    rofecoxib, and nitric oxide NSAIDs;-   (o) insulin-like growth factor type I (IGF-1) mimetics;-   (p) ciclesonide;-   (q) inhalation glucocorticoids with reduced systemic side effects,    including prednisone, prednisolone, flunisolide, triamcinolone    acetonide, beclomethasone dipropionate, budesonide, fluticasone    propionate and mometasone furoate;-   (r) tryptase inhibitors;-   (s) platelet activating factor (PAF) antagonists;-   (t) monoclonal antibodies against endogenous inflammatory entities;-   (u) IPL 576;-   (v) anti-tumour necrosis factor (TNFα) agents, including etanercept,    infliximab and D2E7;-   (w) DMARDs, including leflunomide;-   (x) TCR peptides;-   (y) interleukin converting enzyme (ICE) inhibitors;-   (z) IMPDH inhibitors;-   (aa) adhesion molecule inhibitors, including VLA-4 antagonists;-   (bb) cathepsins;-   (cc) MAP kinase inhibitors;-   (dd) glucose 6-phosphate dehydrogenase inhibitors;-   (ee) kinin B₁ and B₂ receptor antagonists;-   (ff) gold in the form of an aurothio group together with various    hydrophilic groups;-   (gg) immunosuppressive agents, for example cyclosporine,    azathioprine, and methotrexate;-   (hh) anti-gout agents, for example colchicine;-   (ii) xanthine oxidase inhibitors, for example allopurinol;-   (jj) uricosuric agents, for example probenecid, sulfinpyrazone and    benzbromarone;-   (kk) antineoplastic agents, especially antimitotic medicaments    including the vinca alkaloids, such as vinblastine and vincristine;-   (ll) agents for promoting growth hormone secretion;-   (mm) inhibitors of matrix metalloproteases (MMPs), i.e. the    stromelysins, collagenases and gelatinases, as well as aggrecanase,    in particular collagenase-1 (MMP-1), collagenase-2 (MMP-8),    collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2    (MMP-10) and stromelysin-3 (MMP-11);-   (nn) transforming growth factor (TGFβ);-   (oo) platelet-derived growth factor (PDGF);-   (pp) fibroblast growth factor, for example basic fibroblast growth    factor (bFGF);-   (qq) granulocyte macrophage colony stimulating factor (GM-CSF);-   (rr) capsaicin;-   (ss) tachykinin NK₁ and NK₃ receptor antagonists selected from the    group consisting of NKP-608C; SB-233412 (talnetant); and D-4418;-   (tt) elastase inhibitors selected from the group consisting of UT-77    and ZD-0892; and-   (uu) adenosine A2a receptor agonists.    Pharmaceutical Compositions and Fromulations

The description which follows relates to the manner in which thecompounds of the formula I, if desired together with other therapeuticagents or non-therapeutic agents, are combined with predominantlyconventional pharmaceutically acceptable excipients to form dosage formswhich are suitable for the different routes of administration which areutilised for any given patient, and appropriate to the disease,pathological disorder or condition for which a given patient is beingtreated.

The pharmaceutical compositions according to the invention comprise anyone or more of the above-described inhibitory compounds according to theinvention or a pharmaceutically acceptable salt thereof as alsoabove-described, together with a pharmaceutically acceptable excipientin accordance with the properties and expected behaviour of suchexcipients which are well-known to the person skilled in the art.

The amount of active ingredient that can be combined with the excipientmaterials to form a single dosage form varies depending upon the patientbeing treated and the particular method of administration. However, itis clear that a certain dosage and treatment regime for a particularpatient depends on a variety of factors, including the activity of thespecific compound employed, the age, body weight, general state ofhealth, sex, diet, time of administration, excretion rate, medicamentcombination, and the judgment of the treating physician and the severityof the particular disease being treated. The amount of active ingredientmay also depend on the therapeutic or prophylactic agent, if any, withwhich the ingredient is jointly administered.

The compounds of the formula I can be used in the form of acids, esters,or other chemical classes of compound to which the compounds describedbelong. It is also within the scope of the present invention to usethese compounds in the form of pharmaceutically acceptable salts derivedfrom various organic and inorganic acids and bases. An active ingredientcomprising a preferred compound is often used in the form of one of itssalts, in particular if this salt form provides the active ingredientwith improved pharmacokinetic properties compared with the free form ofthe active ingredient or another salt form of the active ingredient usedpreviously. It may also be the case that only the pharmaceuticallyacceptable salt form of the active ingredient provides the activeingredient with a desired pharmacokinetic property which it did notpreviously possess, and may even have a positive effect on thepharmacodynamics of this active ingredient with respect to itstherapeutic activity in the body.

The pharmacokinetic properties of the active ingredient which may befavourably affected include, for example, the manner in which thisactive ingredient is transported through cell membranes, which in turncan have a direct and positive effect on the absorption, distribution,biotransformation and excretion of this active ingredient. Although themethod of administration of the pharmaceutical composition is important,and various anatomical, physiological and pathological aspects cancrucially affect bioavailability, the solubility of the activeingredient is usually dependent on the nature of the particular saltform thereof which is being used. Furthermore, it is clear to the personskilled in the art that an aqueous solution of the active ingredientprovides the fastest absorption of the active ingredient into the bodyof a patient being treated, while lipid solutions and suspensions, aswell as solid dosage forms, result in less rapid absorption of theactive ingredient. Oral ingestion of an active ingredient of the formulaI is the most preferred method of administration for reasons of safety,convenience and economy, but absorption of an oral dosage form of thistype may be adversely affected by physical properties, such as polarity,vomiting caused by irritation of the gastrointestinal mucous membrane,degradation by digestive enzymes and low pH, irregular absorption orpropulsion in the presence of food or other medicaments, and metabolismby enzymes of the mucous membrane, the intestinal flora, or the liver.Formulation of the active ingredient as different pharmaceuticallyacceptable salt forms may be effective in overcoming or alleviating oneor more of the above- mentioned problems in connection with theabsorption of oral dosage forms.

The preferred pharmaceutical salts mentioned above include, but are notlimited to, acetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine.

If a compound of the formula I contains more than one group which iscapable of forming pharmaceutically acceptable salts of this type, theinvention also covers multiple salts. Typical multiple salt formsinclude, but are not limited to, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride.

The pharmaceutical compositions according to the invention comprise oneor more of the above-described inhibitor compounds, or apharmaceutically acceptable salt thereof as also described above,together with a pharmaceutically acceptable excipient in accordance withthe properties and expected behaviour of such excipients which arewell-known to the person skilled in the art.

The term “excipient” in the present connection includes acceptablediluents, carriers, adjuvants, constituents, solubilisers, viscositymodifiers, preservatives and other agents which are well known to theperson skilled n the art for providing the final pharmaceuticalcomposition with favourable properties. In order to illustrate theseexcipients, there follows a brief review of pharmaceutically acceptableexcipients which can be used in the pharmaceutical compositionsaccording to the invention, and thereafter a more detailed descriptionof the various types of constituents. Typical excipients include, butare by no means limited to, ion exchange compositions, alumina,aluminium stearate, lecithin, serum proteins, for example human serumalbumin, phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, hydrogenated palmoils, water, salts or electrolytes, for example prolamine sulfate,disodium hydrogen phosphate, potassium hydrogen phosphate, sodiumchloride and zinc salts, colloidal silica, magnesium trisilicate,polyvinylpyrrolidone, cellulose-based substances, for example sodiumcarboxymethylcellulose, polyethylene glycol, polyacrylates, waxes,polyethylene-polyoxypropylene block polymers and wool fat.

In particular, the excipients used in the pharmaceutical compositionsaccording to the invention include various classes and types ofadditives which are selected independently from the groups essentiallymentioned in the following paragraphs.

Acidifying and alkalising agents are added to obtain a desired orpredetermined pH; they comprise acidifying agents, for example aceticacid, glacial acetic acid, malic acid and propionic acid. Strongeracids, such as hydrochloric acid, nitric acid and sulfuric acid, can beused, but are less preferred. Alkalising agents include, for exampleedetol, potassium carbonate, potassium hydroxide, sodium borate, sodiumcarbonate and sodium hydroxide. Alkalising agents which contain activeamine groups, such as diethanolamine and trolamine, can also be used.

Aerosol propellants are required if the pharmaceutical composition is tobe delivered as an aerosol under significant pressure. Such propellantsinclude, for example acceptable chlorofluorocarbons, such asdichlorodifluoromethane, dichlorotetrafluoroethane andtrichloromonofluoromethane, nitrogen, a volatile hydrocarbon, such asbutane, propane, isobutane, or mixtures thereof.

Antimicrobial agents, including antibacterial, antifungal andantiprotozoal agents, are added if the pharmaceutical composition isapplied topically to areas of the skin which are likely to have sufferedadverse conditions or sustained abrasions or cuts which make the skinsusceptible to infection by bacteria, fungi or protozoa. Antimicrobialagents include compounds such as benzyl alcohol, chlorobutanol,phenylethyl alcohol, phenylmercuric acetate, potassium sorbate andsorbic acid. Antifungal agents include compounds such as benzoic acid,butylparaben, ethylparaben, methylparaben, propylparaben and sodiumbenzoate.

Antimicrobial preservatives are added to the pharmaceutical compositionsaccording to the invention in order to protect them against the growthof potentially harmful microorganisms, which usually invade the aqueousphase, but in some cases can also grow in the oil phase of acomposition. Thus, preservatives with both aqueous and lipid solubilityare desired. Suitable antimicrobial preservatives include, for examplealkyl p-hydroxybenzoates, propionate salts, phenoxyethanol,methylparabensodium, propylparaben-sodium, sodium dehydroacetate,benzalkonium chloride, benzethonium chloride, benzyl alcohol, hydantoinderivatives, quaternary ammonium compounds and cationic polymers,imidazolidinylurea, diazolidinylurea and trisodium ethylenediaminetetraacetate (EDTA).

Preservatives, are preferably employed in amounts of from about 0.01 %by weight to about 2.0% by weight of the total composition.

Antioxidants are added to protect all the ingredients of thepharmaceutical composition from damage or degradation by oxidantspresent in the composition itself or in the environment in which theyare used, for example anoxomer, ascorbyl palmitate, butylhydroxyanisole,butylhydroxytoluene, hypophosphorous acid, potassium metabisulfite,propyl, octyl and dodecyl gallate, sodium metabisulfite, sulfur dioxideand tocopherols.

Buffer substances are used to maintain a desired pH of a composition,once established, from the effects of external influences andequilibrium shifts of constituents of the composition. The buffersubstance can be selected from those known to the person skilled in theart of the preparation of pharmaceutical compositions, for examplecalcium acetate, potassium metaphosphate, potassium dihydrogenphosphateand tartaric acid.

Chelating agents serve to maintain the ionic strength of thepharmaceutical composition; they bind to and thereby effectively removeharmful compounds and metals. These include, for example, dipotassiumedetate, disodium edetate and EDTA.

Dermatological active according to the invention the present inventionwhere they are to be applied topically; they include, for example, woundhealing agents, such as peptide derivatives, yeast, panthenol,hexylresorcinol, phenol, tetracycline hydrochloride, lamin and kinetin;retinoids for treating skin cancer, for example retinol, tretinoin,isotretinoin, etretinate, acitretin and arotinoid, mild antibacterialagents for the treatment of skin infections, for example resorcinol,salicylic acid, benzoyl peroxide, erythromycin-benzoyl peroxide,erythromycin and clindamycin; antifungal agents for the treatment oftinea corporis, tinea pedis, candidiasis and tinea versicolor, forexample griseofulvin, azoles, such as miconazole, econazole,itraconazole, fluconazole and ketoconazole and allylamines, such asnaftifine and terfinafine, antiviral agents for the treatment of herpessimplex of the skin, shingles and chickenpox, for example acyclovir,famciclovir and valacyclovir, antihistamines for treating pruritis,atopic and contact dermatitis, for example diphenhydramine, terfenadine,asternizole, loratadine, cetirizine, acrivastine and temelastine,topical anesthetics for relieving pain, irritation and itquing, forexample benzocaine, lidocaine, dibucaine and pramoxine hydrochloride,topical analgesics for relieving pain and inflammation, for examplemethyl salicylate, camphor, menthol and resorcinol, topical antisepticsfor the prevention of infection, for example benzalkonium chloride andpovidone-iodine, and vitamins and derivatives thereof, such astocopherol, tocopherol acetate, retinoic acid and retinol.

Dispersing and suspending agents are used as aids in the preparation ofstable formulations and include, for example poligeenan, povidone andsilicon dioxide.

Emollients are preferably non-oily and water-soluble agents which softenand soothe the skin, especially skin that has become dry due toexcessive loss of water. Such substances are used with pharmaceuticalcompositions according to the invention which are intended for topicalapplication; they include, for example, hydrocarbon oils and waxes,triglyceride esters, acetylated monoglycerides, methyl and other alkylesters of C₁₀-C₂₀-fatty acids, C₁₀-C₂₀-fatty acids, C₁₀-C₂₀-fattyalcohols, lanolin and derivatives, polyhydric alcohol esters, such aspolyethylene glycol (200-600), polyoxyethylene sorbitan fatty acidesters, wax esters, phospholipids and sterols; emulsifiers for thepreparation of oil-in-water emulsions; excipients, for examplelaurocapram and polyethylene glycol monomethyl ether; humectants, forexample sorbitol, glycerol and hyaluronic acid; ointment bases, forexample Vaseline, polyethylene glycol, lanolin and poloxamer;penetration enhancers, for example dimethyl isosorbide, diethyl glycolmonoethyl ether, 1-dodecylazacycloheptan-2-one and dimethyl sulfoxide(DMSO); preservatives, for example benzalkonium chloride, benzethoniumchloride, alkyl p-hydroxybenzoates, hydantoin derivatives,cetylpyridinium chloride, propylparaben, quarternary ammonium compounds,such as potassium benzoate and thimerosal; sequestering agents,including cyclodextrins, solvents, for example acetone, alcohol, amylenehydrate, butyl alcohol, corn oil, cottonseed oil, ethyl acetate,glycerol, hexylene glycol, isopropyl alcohol, isostearyl alcohol, methylalcohol, methylene chloride, mineral oil, peanut oil, phosphoric acid,polyethylene glycol, polyoxypropylene 15 stearyl ether, propyleneglycol, propylene glycol diacetate, sesame oil and purified water,stabilisers, for example calcium saccharate and thymol, surfacetants,for example lapyrium chloride, laureth 4, i.e.α-dodecyl-ω-hydroxypoly(oxy-1,2-ethanediyl) or polyethylene glycolmonododecyl ether.

Emulsifiers, including emulsifying and thickening agents and emulsionaids, are used for the preparation of oil-in-water emulsions if theseform the basis of the pharmaceutical compositions according to theinvention. These emulsifiers include, for example non-ionic emulsifiers,such as C₁₀-C₂₀ fatty alcohols and the products of the condensation ofthese fatty alcohols with from 2 to 20 mol of ethylene oxide orpropylene oxide, the product of the condensation of (C₆-C₁₂)alkylphenolswith from 2 to 20 mol of ethylene oxide, mono- and di-C₁₀-C₂₀ fatty acidesters of ethylene glycol, C₁₀-C₂₀ fatty acid monoglyceride, diethyleneglycol, polyethylene glycols having an MW of 200 6000, polypropyleneglycols having an MW of 200-3000 and in particular sorbitol, sorbitan,polyoxyethylene sorbitol, polyoxyethylene sorbitan, hydrophilic waxesters, cetostearyl alcohol, oleyl alcohol, lanolin alcohols,cholesterol, mono- and diglycerides, glyceryl monostearate, polyethyleneglycol monostearate, mixed mono- and distearic esters of ethylene glycoland polyoxyethylene glycol, propylene glycol monostearate andhydroxypropylcellulose. Emulsifiers which contain active amine groupscan also be used; these typically include anionic emulsifiers, such asfatty acid soaps, for example sodium, potassium and triethanolaminesoaps of C₁₀-C₂₀ fatty acids, alkali metal, ammonium or substitutedammonium (C₁₀-C₃₀)alkylsulfates, (C₁₀-C₃₀)-alkylsulfonates and(C₁₀-C₅₀)alkyl ethoxyether sulfonates. Other suitable emulsifiersinclude castor oil and hydrogenated castor oil, lecithin, and polymersof 2-propenoic acid together with polymers of acrylic acid, bothcross-linked with allyl ethers of sucrose and/or pentaerythritol, havingvarying viscosities and identified by product names carbomer 910, 934,934P, 940, 941 and 1342. Cationic emulsifiers having active amine groupsmay also be used, including those based on quaternary ammonium,morpholinium and pyridinium compounds. Similarly, amphoteric emulsifiershaving active amine groups, such as cocobetaines, lauryldimethylamineoxide and cocoylimidazoline, can be used. Emulsifiers and thickeningagents that can be used also include cetyl alcohol and sodium stearate,and emulsion aids, such as oleic acid, stearic acid and stearyl alcohol.

Excipients include, for example, laurocapram and polyethylene glycolmonomethyl ether.

If the pharmaceutical composition according to the invention is to beapplied topically, penetration enhancers can be used, including, forexample, dimethyl isosorbide, diethyl glycol monoethylether,1-dodecylazacycloheptan-2-one and dimethyl sulfoxide (DMSO). Suchcompositions typically also comprise ointment bases, for exampleVaseline, polyethylene glycol, lanolin and poloxamer, which is apolyoxyethylene-polyoxypropylene block copolymer, which may also serveas surfactant or emulsifier.

Preservatives are used to protect pharmaceutical compositions accordingto the invention against degradation by ambient microorganisms, andinclude, for example, benzalkonium chloride, benzethonium chloride,alkyl p-hydroxybenzoates, hydantoin derivatives, cetylpyridiniumchloride, monothioglycerol, phenol, phenoxyethanol, methylparagen,imidazolidinyl urea, sodium dehydroacetate, propylparaben, quaternaryammonium compounds, especially polymers, such as polixetonium chloride,potassium benzoate, sodium formaldehyde sulfoxylate, sodium propionateand thimerosal.

Sequestering agents are used to improve the stability of thepharmaceutical compositions according to the invention; they include,for example, the cyclodextrins, which are a family of natural cyclicoligosaccharides which are capable of forming inclusion complexes with avariety of substances and are of varying ring size, those having 6, 7and 8 glucose radicals per ring usually being referred to asα-cyclodextrins, β-cyclodextrins and γ-cyclodextrins, respectively.Suitable cyclodextrins include, for example α-cyclodextrin,β-cyclodextrin, γ-cyclodextrin, δ-cyclodextrin and cationisedcyclodextrins.

Solvents which may be used in the preparation of the pharmaceuticalcompositions according to the invention include, for example, acetone,alcohol, amylene hydrate, butyl alcohol, corn oil, cottonseed oil, ethylacetate, glycerol, hexylene glycol, isopropyl alcohol, isostearylalcohol, methyl alcohol, methylene chloride, mineral oil, peanut oil,phosphoric acid, polyethylene glycol, polyoxypropylene 15 stearyl ether,propylene glycol, propylene glycol diacetate, sesame oil and purifiedwater.

Stabilisers which are suitable for use include, for example calciumsaccharate and thymol.

Thickening agents are typically used in formulations for topicalapplication in order to provide these with the desired viscosity and thedesired handling properties; they include, for example, cetyl ester wax,myristyl alcohol, paraffin, synthetic paraffin, emulsifying wax,microcrystalline wax, bleached wax and yellow wax.

Sugars are frequently used to provide the pharmaceutical compositionsaccording to the invention with various desired properties and toimprove the results achieved; they include, for example,monosaccharides, disaccharides and polysaccharides, such as glucose,xylose, fructose, reose, ribose, pentose, arabinose, allose, tallose,altrose, mannose, galactose, lactose, sucrose, erythrose,glyceraldehyde, or any combination thereof.

Surfactants are employed to provide multi-component pharmaceuticalcompositions according to the invention with stability, to enhanceexisting properties of these compositions, and to provide thecompositions with new desired properties. Surfactants are used aswetting agents, anti-foams, for reducing the surface tension of water,and as emulsifiers, dispersants and penetration enhancers; they include,for example lapyrium chloride, laureth 4, i.e.α-dodecyl-ω-hydroxy-poly(oxy-1,2-ethanediyl) or polyethylene glycolmonododecyl ether, laureth 9, i.e. a mixture of polyethylene glycolmonododecyl ethers having an average of 9 ethylene oxide groups permolecule, monoethanolamine, nonoxynol-4, -9 and -10, i.e. polyethyleneglycol mono(p-nonylphenyl) ether, nonoxynol 15, i.e.α-(p-nonylphenyl)-ω-hydroxypentadeca(oxyethylene), nonoxynol 30, i.e.α-(p-nonylphenyl)-ω-hydroxytriaconta(oxyethylene), poloxalene, i.e.nonionic polymer of the polyethylenepolypropylene glycol type,MW=approx. 3000, poloxamer, referred to above in the discussion ofointment bases, polyoxyl (8), (40) and (50) stearate, i.e.poly(oxy-1,2-ethanediyl), α-hydro-ω-hydroxy-octadecanoate, polyoxyl (10)oleyl ether, i.e. poly(oxy-1,2-ethanediyl),α-[(Z)-9-octadecenyl-ω-hydroxy-, polysorbate 20, i.e. sorbitan,monododecanoate, poly(oxy-1,2-ethanediyl), polysorbate 40, i.e.sorbitan, monohexadecanoate, poly(oxy-1,2-ethanediyl), polysorbate 60,i.e. sorbitan, monooctadecanoate, poly(oxy-1,2-ethanediyl), polysorbate65, i.e. sorbitan, trioctadecanoate, poly(oxy-1,2-ethanediyl),polysorbate 80, i.e. sorbitan, mono-9 -monodecenoate,poly(oxy-1,2-ethanediyl), polysorbate 85, i.e. sorbitan,tri-9-octadecenoate, poly(oxy-1,2-ethanediyl), sodium lauryl sulfate,sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate,sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, andsorbitan tristearate.

The pharmaceutical compositions according to the invention can beprepared in an extremely simple manner as is well known to the averageperson skilled in the art. If the pharmaceutical compositions accordingto the invention are simple aqueous solutions or solutions in othersolvents, the various constituents of the overall composition arecombined in any desired practical sequence, which is determinedprincipally by considerations of convenience. The constituents that havelower solubility in water, but adequate solubility in the same auxiliarysolvent with water, can all be dissolved in this auxiliary solvent,after which the auxiliary solution is added to the water content of theexcipient, causing the substances dissolved therein to dissolve in thewater. To support this dispersion process or dissolution process, asurfactant can be employed.

If the pharmaceutical compositions according to the invention are in theform of emulsions, the constituents of the pharmaceutical compositionare combined in accordance with the following general procedures. Thecontinuous water phase is firstly heated to a temperature in the rangefrom about 60° C. to about 95° C., preferably from about 70° C. to about95° C., with the choice of temperature used depending on the physicaland chemical properties of the constituents which form the oil-in-wateremulsion. As soon as the continuous water phase has reached the selectedtemperature, the constituents of the final composition which are to beadded at this stage are mixed with the water with vigorous stirring anddispersed therein. Next, the temperature of the water is restoredapproximately to the initial level, after which the constituents of thecomposition which form the next step are added to the compositionmixture with morate stirring, and mixing is continued for from about 5to about 60 minutes, preferably from about 10 to about 30 minutes,depending on the constituents of the first two steps. The compositionmixture is then passively or actively cooled to from about 20° C. toabout 55° C. in order that further components can be added in theremaining steps, after which sufficient water is added that theoriginally determined concentration in the overall composition isreached.

In accordance with the present invention, the pharmaceuticalcompositions can be in the form of a sterile injection preparation, forexample a sterile aqueous or oil-based suspension for injection. Thissuspension can be formulated in accordance with techniques known in theart using suitable dispersants or wetting agents and suspension media.The sterile injection preparation can also be a sterile solution orsuspension for injection in a non-toxic parenterally acceptable diluentor solvent, for example in the form of a solution in 1,3-butanediol.Acceptable constituents and solvents which can be used include water,Ringer's solution and isotonic saline solution. In addition, sterilestabilised oils are usually used as solvent or suspension medium. Forthis purpose, any mild stabilised oil, including synthetic mono- ordiglycerides, can be used. Fatty acids, such as oleic acid and itsglyceride derivatives, are suitable for the preparation of injectables,as are natural pharmaceutically acceptable oils, such as olive oil orcastor oil, in particular in the form of their polyoxyethylates. Theseoil solutions or suspensions can also contain a long-chain alcohol, suchas Rh, HCIX or a similar alcohol, as diluent or dispersant.

The pharmaceutical compositions according to the invention can beadministered orally in any orally acceptable dosage form, including, butnot limited to, capsules, tablets, aqueous suspensions or solutions. Inthe case of oral tablets, excipients which are frequently used includelactose and corn starch. Lubricants, such as magnesium stearate, arealso typically added. In the case of oral administration in capsuleform, useful diluents include lactose and dried corn starch. If aqueoussolutions are to be used orally, the active ingredient is combined withemulsifiers and suspension media. If desired, certain sweeteners,flavours or dyes can also be added. However, the pharmaceuticalcompositions according to the invention can also be administered in theform of suppositories for rectal administration. Such suppositories canbe produced by mixing the agent with a suitable non-irritating excipientwhich is solid at room temperature, but liquid at the rectal temperatureand therefore melts in the rectum and thus releases the medicament.These substances include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions according to the invention can also beadministered topically, in particular if areas or organs that arereadily accessible by topical application form the target of treatment,including eye diseases, skin diseases, or diseases of the lowerintestinal tract.

Suitable topical formulations can easily be prepared for these areas ororgans.

Topical application for the lower intestinal tract can be effected as arectal suppository formulation, as described above, or in the form of asuitable enema formulation. Topically active transdermal patches canlikewise be used.

For topical application, the pharmaceutical compositions can beformulated as a suitable ointment comprising the active constituentsuspended or dissolved in one or more excipients. Excipients for topicaladministration of the compounds according to the invention include, butare not limited to, mineral oil, paraffin oil, white Vaseline, propyleneglycol, polyoxyethylene-polyoxypropylene compound, emulsifying wax andwater. However, the pharmaceutical compositions can also be formulatedas a suitable lotion or cream comprising the active constituentssuspended or dissolved in one or more pharmaceutically acceptableexcipients. Suitable excipients include, but are not limited to, mineraloil, sorbitan monostearate, polysorbate, cetyl ester wax, cetearylalcohol, 2-octyldodecanol, benzyl alcohol and water.

Pharmaceutical compositions to which the present compound extends alsoinclude those in which the therapeutically effective amount of an activeingredient comprising a compound of the formula I which is required forthe treatment or prevention of diseases, pathological disorders andconditions which are mediated by or associated with modulation of PDE IVactivity as described herein, is provided in a dosage form which issuitable for systemic administration. A pharmaceutical composition ofthis type comprises the active ingredient in a suitable liquid form fordelivery by: (1) injection or infusion, be it intraarterially, intra- ortransdermally, subcutaneously, intramuscularly, intraspinally,intrathecally or intravenously, where the active ingredient: (a) is inthe form of a dissolved substance in solution, (b) is present in thediscontinuous phase of an emulsion or in the discontinuous phase of anemulsion with phase reversal, in which the phase inverts on injection orinfusion, where emulsions of this type comprise suitable emulsifiers, or(c) is present as a suspended solid in colloidal or microparticulateform in a suspension, where this suspension comprises suitablesuspension media, (2) injection or infusion into suitable body tissuesor cavities as a depot, where the composition stores the activeingredient and subsequently releases it for systemic distribution in theform of a delayed, sustained or controlled release, (3) instillation,inhalation or insufflation of the pharmaceutical composition in asuitable solid form into suitable body tissues or cavities, where theactive ingredient: (a) is present in a solid implant of the compositionwhich ensures release of the active ingredient in the form of delayed,sustained or controlled release, (b) is present in a particulatecomposition to be inhaled into the lungs, or (c) is present in aparticulate composition to be blown into suitable body tissues orcavities, where the composition is, if desired, ready for the release ofthe active ingredient in the form of delayed, sustained or controlledrelease, or (4) ingestion of the pharmaceutical composition in asuitable solid or liquid form for peroral delivery of the activeingredient, where the active ingredient is present in a solid dosageform, or (b) is present in a liquid dosage form.

Individual dosage forms of the above-described pharmaceuticalcompositions include (1) suppositories as a special type of implant,comprising bases which are solid at room temperature, but melt at bodytemperature and thus slowly release the active ingredient they containinto the surrounding body tissue, where the active ingredient isabsorbed and transported to effect systemic administration, (2) solidperoral dosage forms selected from the group consisting of (a)delayed-release oral tablets, capsules, caplets, lozenges, troches andmultiparticulates, (b) entericcoated tablets and capsules which preventrelease and absorption in the stomach and thus enable delivery distal tothe stomach of the patient being treated, (c) sustained-release oraltablets, capsules and microparticulates which provide systemic deliveryof the active ingredient in a controlled manner over a period of up to24 hours, (d) fast-disintegrating tablets, (e) encapsulated solutions,(f) oral pastes, (g) granules incorporated into the food of a patientbeing treated, and (h) liquid peroral dosage forms selected from thegroup consisting of solutions, suspensions, emulsions, inverseemulsions, elixirs, extracts, tinctures and concentrates.

Pharmaceutical compositions to which the present compound extends alsoinclude those in which the therapeutically effective amount of an activeingredient comprising a compound according to the invention which isrequired for the treatment or prevention of diseases, pathologicaldisorders and conditions which are mediated by or associated withmodulation of PDE IV activity as described herein is provided in adosage form which is suitable for local administration to a patientbeing treated, where a pharmaceutical composition of this type comprisesthe active ingredient in suitable liquid form for delivery of the activeingredient by (1) injection or infusion, be it intraarterially,intraarticularly, intrachohdrially, intracostally, intracysticly, intra-or transdermally, intrafasicularly, intraligamentously, intramedularly,intramuscularly, intranasally, intraneurally, intraocularly, i.e.opthalmic administration, intraosteally, intrapelvicly,intrapericardially, intraspinally, intrasternally, intrasynovially,intratarsally or intrathecally, also including constituents which ensuredelayed release, controlled release or sustained release of the activeingredient into this local site; where the active ingredient is (a) isin the form of a dissolved substance in solution, (b) is present in thediscontinuous phase of an emulsion or in the discontinuous phase of anemulsion with phase reversal, in which the phase inverts on injection orinfusion, where emulsions of this type comprise suitable emulsifiers, or(c) is present as a suspended solid in colloidal or microparticulateform in a suspension, where this suspension comprises suitablesuspension media, or (2) is in the form of an injection or infusion as adepot for release of the active ingredient at the local site, where thecomposition stores the active ingredient and subsequently releases it tothe local site in the form of delayed release, sustained release orcontrolled release, where the composition also comprises constituentswhich ensure that the active ingredient primarily acts locally andcauses little systemic carryover, or where the pharmaceuticalcomposition comprises the active ingredient in a suitable solid form fordelivery of the inhibitor b the following method: (3) instillation,inhalation or insufflation at this local site, where the activeingredient is present in: (a) a solid implant of the composition whichis implanted at this local site, where the composition releases theactive ingredient to the said local site optionally in the form ofdelayed release, sustained release or controlled release, (b) in aparticulate composition which is inhaled into a local site, alsoincluding the lungs, or (c) in a particulate composition which is blowninto a local site, where the composition comprises constituents whichensure that the active ingredient primarily acts locally, withinsignificant systemic carryover, and optionally releases the activeingredient locally in the form of delayed release, sustained release orcontrolled release. For ophthalmic use, the pharmaceutical compositionscan be formulated as micronised suspension in isotonic, pH adjustedsterile saline solution, or, preferably, as solutions in isotonic, pHadjusted sterile saline solution, with or without preservatives, such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutical compositions can be formulated in an ointment, such asVaseline.

The pharmaceutical compositions according to the invention can also beadministered by nasal aerosol or inhalation using a nebuliser, drypowder inhaler or dispensing inhaler. Such compositions are prepared bytechniques which are well-known in pharmaceutical formulation and can beprepared in the form of solutions in saline solution with benzyl alcoholor other suitable preservatives, absorption promoters for improvingbioavailability, fluorohydrocarbons and/or other conventionalsolubilising agents or dispersants.

As already mentioned, the compounds of the formula I according to theinvention can be administered systemically to a patient to be treated inthe form of a pharmaceutical composition in a suitable liquid form byinjection or infusion. There are various sites and organ systems in thebody of the patient which will allow the correctly formulatedpharmaceutical composition, as soon as it has been injected or infused,to permeate the entire body and all organ systems of the patient beingtreated. An injection is a single dose of the pharmaceutical compositionforced, usually by means of a syringe, into the relevant tissue. Themost frequent types of injection are intramuscular, intravenous andsubcutaneous. By contrast, an infusion is the gradual introduction ofthe pharmaceutical composition into the relevant tissue. The mostfrequent type of infusion is intravenous. Other types of injection orinfusion include intraarterial, intra- or transdermal (includingsubcutaneous), or intraspinal, in particular intrathecal. In theseliquid pharmaceutical compositions, the active ingredient may be in theform of a dissolved substance in solution. This is the commonest andmost preferred type of such a composition, but requires an activeingredient in salt form that has reasonably good solubility in water.Water (or saline solution) is by far the most preferred solvent for suchcompositions. Occasionally supersaturated solutions can be used, butthese present stability problems and are therefore impractical foreveryday use.

If it is not possible to obtain a preferred compound in a form which hasthe requisite solubility in water, as is sometimes the case, it iswithin the skill of the average person skilled in the art to prepare anemulsion, which is a dispersion of small droplets of a liquid, thediscontinuous or internal phase, in a second liquid, the continuous orexternal phase, with which it is immiscible. The two liquids are kept inthe emulsified state by pharmaceutically acceptable emulsifiers. If theactive ingredient is a water-in-soluble oil, it can therefore beadministered in an emulsion in which it forms the discontinuous phase.If the active ingredient is water-insoluble, but can be dissolved in awater-immiscible solvent, an emulsion can likewise be used. Although theactive ingredient would most frequently be used as the discontinuous orinternal phase of a so-called oil-in-water emulsion, it could also beused as the discontinuous or internal phase of an emulsion with phaseinversion, which is usually referred to as a water-in-oil emulsion.Here, the active ingredient is soluble in water and could beadministered as a simple aqueous solution. However, emulsions of thistype with phase inversion invert on injection or infusion into anaqueous medium, such as the blood, and offer the advantage of faster andmore efficient dispersion of the active ingredient into this aqueousmedium than on use of an aqueous solution. Emulsions with phaseinversion are prepared using suitable pharmaceutically acceptableemulsifiers that are well known in the art. granulomas containingeosinophils, allergic granulornatous angijtis' or ChurgStrauss syndrome,

If the active ingredient has limited water solubility, it can also beadministered as a suspended solid in colloidal or finely divided form ina suspension prepared using suitable pharmaceutically acceptablesuspension media. The suspended solids comprising the active ingredientmay also be formulated as delayed release, sustained release orcontrolled release compositions.

Although systemic administration is most frequently carried out byinjection or infusion of a liquid, there are many situations in which itis advantageous or even necessary to deliver the active ingredient as asolid. Systemic administration of solids is carried out by instillation,inhalation or insufflation of a pharmaceutical composition in a suitablesolid form comprising the active ingredient. Instillation of the activeingredient may entail inserting a solid implant of the composition intosuitable body tissues or cavities. The implant may comprise a matrix ofbiocompatible and bioerodible materials in which particles of a solidactive ingredient are dispersed, or in which droplets or isolated cellsof a liquid active ingredient may possibly be included. The matrixshould wherever possible be broken down and completely absorbed by thebody. The composition of the matrix is also preferably selected so as toprovide controlled release, sustained release or delayed release of theactive ingredient over extended periods of time, even several months.

The term “implant” usually refers to a solid pharmaceutical compositioncomprising the active ingredient, while the term “depot” usually denotesa liquid pharmaceutical composition comprising the active ingredient,which is deposited in any suitable body tissue or any suitable bodycavity and thus forms a reservoir or pool which slowly migrates into thesurrounding tissue and organs and finally and eventually is systemicallydistributed. However, these distinctions are not always handled strictlyto in the art, and it is therefore intended that the scope of thepresent invention also extends to liquid implants and solid depots, andeven solid and liquid mixed forms in each case. Suppositories can beregarded as a type of implant, since they comprise bases which are solidat room temperature, but melt at a patient's body temperature and thusslowly release the active ingredient with which they are provided intothe surrounding tissue f the patient's body, where the active ingredientis absorbed and transported away and is thus administered systemically.

Systemic administration can also be carried out by inhalation orinsufflation of a powder, i.e. a particulate composition comprising theactive ingredient. For example, the active ingredient in powder form maybe inhaled into the lungs using conventional devices for aerosolformation of particulate formulations. The active ingredient as aparticulate formulation can also be administered by insufflation, i.e.blown or otherwise dispersed into suitable body tissues or cavities bysimple dusting or using conventional devices for aerosol formation ofparticulate formulations. These particulate compositions can likewise beformulated in accordance with well-known principles and with knownmaterials to give an active ingredient with delayed release, sustainedrelease or controlled release.

Other means of systemic administration, in which the active ingredientsaccording to the invention are used either in liquid or solid form,include the transdermal, intranasal and ophthalmic administrationroutes. In particular, transdermal patches produced by techniques knownin medicament delivery can be produced and applied to the skin of thepatient to be treated, after which the active ingredient, owing to itsformulated solubility properties, migrates through the epidermis andinto the dermal layers of the patient's skin, where it is taken up aspart of the general circulation of the patient and finally andultimately results in systemic distribution of the active ingredientover a desired, extended period of time. These also include implantswhich are placed beneath the epidermal layer of the skin, i.e. betweenthe epidermis and the dermis of the skin of the patient being treated.Such an implant is formulated in accordance with well known principlesand materials which are frequently used in this delivery technique, andcan be produced in such a way that the active ingredient is deliveredinto the systemic circulation of the patient in accordance with theprinciple of controlled release, sustained release or delayed release.Subepidermal (subcuticular) implants of this type can be used just aseasily as transdermal patches and offer the same effective delivery, butwithout being subjected to the degradation, damage or accidental removalas a consequence of the patch being exposed on the outermost layer ofthe patient's skin.

In the above description of pharmaceutical compositions comprising apreferred compound, the equivalent expressions “administration”,“administration of”, “administering” and “administer a” have been usedwith respect to these pharmaceutical compositions. In the presentconnection, these expressions are intended to mean that a patient inneed of treatment is provided with a pharmaceutical compositionaccording to the invention by any of the methods of administrationdescribed here, where the active ingredient is a preferred compound or aprodrug, a derivative or a metabolite thereof which is suitable for thetreatment of a disease, pathological disorder or condition which ismediated by or associated with modulation of PDE IV activity in thispatient. The present invention therefore extends to any other compoundwhich, on administration to a patient, is capable of directly orindirectly making a preferred compound available. Such compounds areknown as prodrugs, and a large number of established procedures existfor the preparation of such prodrug forms of the preferred compounds.

The dose or dosage of the compounds effective for the treatment orprevention of a disease, pathological disorder or condition which ismediated by or associated with modulation of PDE IV activity depends ona variety of factors, such as the nature of the inhibitor, the size ofthe patient, the aim of the treatment, the nature of the pathology to betreated, the pharmaceutical composition used in each case and theobservations and conclusions of the treating physician.

In the case of an oral dosage form, for example a tablet or capsule,suitable doses of the compounds of the formula I are between about 0.1μg of active ingredient/kg and about 50.0 mg of active ingredient/kg ofbody weight per day, preferably between about 5.0 μg of activeingredient/kg and about 5.0 mg of active ingredient/kg of body weightper day, more preferably between about 10.0 μg of active ingredient/kgand about 1.0 mg of active ingredient/kg of body weight per day, mostpreferably between about 20.0 μg of active ingredient/kg and about 0.5mg of active ingredient/kg of body weight per day of the activeingredient.

If the dosage form is administered topically to the bronchia and lungs,for example by means of a powder inhaler or nebuliser, suitable doses ofthe compounds are between about 0.001 μg of active ingredient/kg andabout 10.0 mg of active ingredient/kg of body weight per day, preferablybetween about 0.5 μg of active ingredient/kg and about 0.5 mg of activeingredient/kg of body weight per day, more preferably between about 1.0μg of active ingredient/kg and about 0.1 mg of active ingredient/kg ofbody weight per day and most preferably between about 2.0 μg of activeingredient/kg and about 0.05 mg of active ingredient/kg of body weightper day of the active ingredient.

In order to explain the range of the daily oral dose that could be usedas described above and with the aid of a typical body weights of 10 kgand 100 kg, suitable doses of the compounds of the formula I are betweenabout 1.0-10.0 μg and 500.0-5000.0 mg of the active ingredientcomprising a preferred compound per day, preferably between about50.0-500.0 μg and 50.0-500.0 mg of the active ingredient comprising apreferred compound per day, more preferably between about 100.0-1000.0μg and 10.0-100.0 mg of the active ingredient comprising a preferredcompound per day and most preferably between about 200.0-2000.0 μg andabout 5.0-50.0 mg of the active ingredient comprising a preferredcompound per day. These dosage ranges represent total doses of theactive ingredient per day for a particular patient. The number of timesper day that a dose is administered depends on pharmacological andpharmacokinetic factors such as the half-life of the active ingredient,which reflects its rate of catabolism and clearance, as well as theminimum and optimum blood plasma level or other body fluid levels of theactive ingredient in a patient which are necessary for therapeuticefficacy.

When determining the number of doses per day and the amount of activeingredient per dose that will be administered, numerous other factorsmust also be considered. Another such factor is not least the particularresponse of the patient being treated. Thus, for example, if the activeingredient is used for the treatment or prevention of asthma on topicaladministration via aerosol inhalation into the lungs, from one to fourdoses consisting of actuations of a dispensing device, i.e. “puffs” ofan inhaler, are administered. per day, each dose comprising from about50.0 μg to about 10.0 mg of active ingredient.

The invention furthermore also relates to medicaments comprising atleast one compound of the formula I and/or pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and, if desired, excipients and/or adjuvants.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and at least one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or    pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios,    -   and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules each containing an effective amount of a compound of theformula I and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilised form.

All temperatures above and below are given in ° C. In the examples whichfollow, “customary work-up” means that water is added if necessary, thepH is adjusted, if necessary, to between 2 and 10, depending on theconstitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the residue is purifiedby chromatography on silica gel and/or by crystallisation.

Mass spectrometry (MS): El (electron impact ionisation) M⁺

-   -   FAB (fast atom bombardment)(M+H)⁺

EXAMPLE 1

1.1 4.3 g of m-chloroperbenzoic acid are added to a solution of 3.5 g ofmethyl 4-methyl-2-pyridin-2-ylthiazole-5-carboxylate in 100 ml of DCM,and the mixture is stirred for a further 16 hours. Conventional work-upgives 2.1 g of methyl4-methyl-2-(1-oxypyridin)-2-ylthiazole-5-carboxylate (“AA”).

1.2 A solution of 2.1 g of “AA” and 3.4 ml of sodium hydroxide solution(32%) in 50 ml of water and 50 ml of methanol is stirred at roomtemperature for 3 hours. Conventional work-up gives 1.7 g of4-methyl-2-(1-oxypyridin)-2-ylthiazole-5-carboxylic acid (“AB”), HPLC-MSm/e 237.

1.3 1.7 g of “AB” and 20 ml of thionyl chloride are refluxed for 2hours. The thionyl chloride is removed, giving 1.8 g of4-methyl-2-(1-oxypyridin)-2-ylthiazole-5-carbonyl chloride (“AC”).

1.4 278 mg of “AC” are added to a mixture of 300 mg of3-(3-cyclopentyloxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine and 1 gof piperidinomethyl-polystyrene in 6 ml of DCM, and the mixture isstirred at room temperature for a further 16 hours. The polymer isremoved, and the filtrate is evaporated in a Genevac® (rotaryevaporator), giving 508 mg of1-[3-(3-cyclopentyloxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-[4-methyl-2-(1-oxypyridin-2-yl)thiazol-5-yl]methanone (“AD”), HPLC-MS m/e 493.

An analogous reaction of “AC” with

-   -   3-(3-isopropoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine,    -   3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine,        gives the following compounds:    -   1-[3-(3-isopropoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl        ]-1-[4-methyl-2-(1-oxypyridin-2-yl)thiazol-5-yl]methanone,        HPLC-MS m/e 467;    -   1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-[4-methyl-2-(1        -oxypyridin-2-yl)thiazol-5-yl]methanone, HPLC-MS m/e 453.

EXAMPLE 2

1 ml of pyridine is added to a solution of 1.1 g of3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine in 20 ml of DCM,and 1.2 g of 4-methyl-2-pyridin-3-ylthiazole-5-carbonyl chloride,hydrochloride (“BA”) are subsequently added, and the mixture is stirredat room temperature for a further 16 hours. Conventional work-up gives1.7 g of1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-pyridin-3-ylthiazol-5-yl)methanone.

An analogous reaction gives the compounds

-   -   1-[3-(3-isopropoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-pyridin-3-ylthiazol-5-yl)methanone,    -   1-[3-(3-cyclopentyloxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-pyridin-3-ylthiazol-5-yl)methanone.

EXAMPLE 3

Analogously to Example 2, reaction of 1.1 g of3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine with 1.2 g of4-methyl-2-pyridin-2-ylthiazole-5-carbonyl chloride, hydrochloride(“BB”) gives the compound1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-pyridin-2-ylthiazol-5-yl)methanone(1.5 g).

An analogous reaction gives the compounds

-   -   1-[3-(3-isopropoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-pyridin-2-ylthiazol-5-yl)methanone,    -   1-[3-(3-cyclopentyloxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-pyridin-2-ylthiazol-5-yl)methanone.

EXAMPLE 4

Analogously to Example 2, reaction of 300 mg of3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine with 307 mg of4-methyl-2-pyrazin-2-yl-thiazole-5-carbonyl chloride (“BC”) gives thecompound1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-pyrazin-2-yl-thiazol-5-yl)methanone(484 mg, HPLC-MS m/e 438).

An analogous reaction of “BC” with

-   -   3-(3-isopropoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine,    -   3-(3-cyclopentyloxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine,        gives the compounds    -   1-[3-(3-isopropoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-pyrazin-2-ylthiazol-5-yl)methanone,        HPLC-MS m/e 452;    -   1-[3-(3-cyclopentyloxy4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-pyrazin-2-ylthiazol-5-yl)methanone,        HPLC-MS m/e 478.

EXAMPLE 5

Analogously to Example 2, reaction of 1.04 g of3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro4H-pyridazine with 1.08 g of4-methyl-2-thiophen-2-ylthiazole-5-carbonyl chloride (“CA”) gives thecompound1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-thiophen-2-ylthiazol-5-yl)methanone(1.54 g).

An analogous reaction gives the compounds

-   -   1-[3-(3-isopropoxy4-methoxyphenyl)-5,6-dihydro4H-pyridazin-1-yl]-1-(4-methyl-2-thiophen-2-ylthiazol-5-yl)methanone,    -   1-[3-(3-cyclopentyloxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-thiophen-2-ylthiazol-5-yl)methanone.

EXAMPLE 6

Analogously to Example 2, reaction of3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine with

-   -   4-methyl-2-phenylthiazole-5-carbonyl chloride,    -   4-methyl-2-(4-methoxyphenyl)thiazole-5-carbonyl chloride,    -   4-methyl-2-(4-BOC-aminophenyl)thiazole-5-carbonyl chloride,        gives the compounds    -   1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-        1-[4-methyl-2-phenylthiazol-5-yl]methanone,    -   1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-[4-methyl-2-(4-methoxyphenyl)thiazol-5-yl]methanone,    -   1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-[4-methyl-2-(4-BOC-aminophenyl)thiazol-5-yl]methanone.

EXAMPLE 7

7.1 Removal of the BOC group from1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-[4-methyl-2-(4-BOC-aminophenyl)thiazol-5-yl]methanoneusing HCI/dioxane gives the compound1-[3-(3-ethoxy4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-[4-methyl-2-(4-aminophenyl)thiazol-5-yl]methanone(“DA”).

7.2 270 mg of “DA” are added to a solution of 0.6 ml of 25% HCl in 10 mlof water. The mixture is cooled to −2°, 48.3 mg of NaNO₂ are added, andthe mixture is stirred for a further 1 hour. 43.5 mg of malononitrileare then added, and the mixture is stirred at room temperature for afurther 1 hour. The mixture is adjusted to pH 5 using saturated sodiumacetate solution, and the precipitated material is filtered off, washedwith water and dried for 16 hours at 50°. The equimolar amount of 0.5 NKOH in methanol is added to the filtrate, and the mixture is evaporated.The residue is recrystallised from ethanol.

Yield: 230 mg of the compound

2-[(4-{5-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine-1-carbonyl]-4-methylthiazol-2-yl}phenyl)hydrazono]malononitrile(“DB”)

7.3 A solution of 500 mg of “DB”, 66 mg of ammonium chloride, 81 mg ofsodium azide and a catalytic amount of lithium chloride in 4 ml of DMFis stirred at 120° for 24 hours. Work-up is carried out in aconventional manner, after which the dried crystals are re-dissolved inmethanol. An equivalent amount of KOH in methanol is added. The solventis removed, and ethyl acetate/diethyl ether is added to the residue.

Yield: 460 mg of the compound

2-[(4-{5-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine-1-carbonyl]4-methylthiazol-2-yl}phenyl)hydrazono]-2-(1H-tetrazol-5-yl)-acetonitrile,potassium salt

An analogous reaction gives the compounds

-   -   2-[(4-{5-[3-(3-cyclopentyloxy4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-carbonyl]-4-methylthiazol-2-yl}phenyl)hydrazono]-2-(1H-tetrazol-5-yl)acetonitrile,    -   2-[(4-{5-[3-(3-isopropoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-carbonyl]-4-methylthiazol-2-yl}phenyl)hydrazono]-2-(1H-tetrazol-5-yl)acetonitrile.

EXAMPLE I Effect of the Compounds of the Formula I on the Proliferationof T-Cells

Peripheral blood monocytes (PBMCs) are isolated from the blood ofhealthy donors by the Lymphoprep gradient method. In each well, 200,000PBMCs are cultivated in RPMI1640 culture medium with 5% ofheat-deactivated human serum (AB pool) for 5 days at 37° C. and 10% CO₂in 96-well flat-base microtitre plates. The T-cells of the PBMC sampleare stimulated selectively against CD3 with a monoclonal antibody. Thecultures are prepared in triplicate, including a control group withouttreatment.

The compounds of the formula I are dissolved in DMSO in a concentrationof 10⁻² M and diluted with culture medium. The control cultures aretreated with DMSO corresponding to the inhibitor concentration.³H-thymidine is added to the cultures 18 hours before the end of theassay.

The uptake of the radioactivity into the cells is then measured using abeta counter.

The values of at least three independent experiments are calculated aspercentage inhibition of the control (mean±SFN) without inhibitor. TheIC₅₀ value is determined from these values.

EXAMPLE II Effect of the Compounds of the Formula I on CytokineProduction in Human Peripheral Blood Monocytes

Peripheral blood monocytes (PBMCs) are isolated from the blood ofhealthy donors by the Lymphoprep gradient method. In each well, 200,000PBMCs are cultivated in RPMI1640 culture medium with 5% ofheat-deactivated human serum (AB pool) at 37° C. and 10% CO₂ in 96-wellflat-base microtitre plates. The cultures are prepared in triplicate,including a control group. Solutions of the compounds of the formula Iin DMSO are prepared in a concentration of 10⁻² M and diluted withculture medium. The control cultures are treated with DMSOconcentrations corresponding to the inhibitor concentrations.

The culture supernatants from three independent experiments are pooled,and the cytokine activity in the supernatant is measured usingcommercially available ELISA test kits.

The data are calculated as percentage inhibition/stimulation of thecontrol without the compound, and the IC₅₀ value or EC₅₀ value duringthe stimulation is determined therefrom.

The examples below relate to pharmaceutical preparations:

EXAMPLE A Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 I of bidistilled water is adjusted to pH6.5 using 2N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient of the formula I is meltedwith 100 g of soya lecithin and 1400 g of cocoa butter, poured intomoulds and allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2 H₂O, 28.48 g of Na₂HPO₄.12 H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 I and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient of the formula 1, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Coated Tablets

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient of the formula I are introduced in aconventional manner into hard gelatine capsules in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 I ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. A compound of the formula a)1-[3-(3-cyclopentyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-[4-methyl-2-(1-oxypyridin-2-yl)thiazol-5-yl]methanone,b)1-[3-(3-isopropoxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-[4-methyl-2-(1-oxypyridin-2-yl)thiazol-5-yl]methanone,c)1-[3-(3-ethoxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-[4-methyl-2-(1-oxypyridin-2-yl)thiazol-5-yl]methanone,d)1-[3-(3-ethoxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-(4-methyl-2-pyridin-3-ylthiazol-5-yl)methanone,e)1-[3-(3-isopropoxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-(4-methyl-2-pyridin-3-ylthiazol-5-yl)methanone,f)1-[3-(3-cyclopentyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-(4-methyl-2-pyridin-3-ylthiazol-5-yl)methanone,g)1-[3-(3-ethoxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-(4-methyl-2-pyridin-2-ylthiazol-5-yl)methanone,h)1-[3-(3-isopropoxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-(4-methyl-2-pyridin-2-ylthiazol-5-yl)methanone,i)1-[3-(3-cyclopentyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-(4-methyl-2-pyridin-2-ylthiazol-5-yl)methanone,j)1-[3-(3-ethoxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-(4-methyl-2-pyrazin-2-ylthiazol-5-yl)methanone,k)1-[3-(3-isopropoxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-(4-methyl-2-pyrazin-2-ylthiazol-5-yl)methanone,l)1-[3-(3-cyclopentyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-(4-methyl-2-pyrazin-2-ylthiazol-5-yl)methanone,m)1-[3-(3-ethoxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-(4-methyl-2-thiophen-2-ylthiazol-5-yl)methanone,n)1-[3-(3-isopropoxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-(4-methyl-2-thiophen-2-ylthiazol-5-yl)methanone,o)1-[3-(3-cyclopentyloxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-(4-methyl-2-thiophen-2-ylthiazol-5-yl)methanone,p)1-[3-(3-ethoxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-[4-methyl-2-phenylthiazol-5-yl]methanone,q)1-[3-(3-ethoxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-[4-methyl-2-(4-methoxyphenyl)thiazol-5-yl]methanone,r)1-[3-(3-ethoxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-yl]-1-[4-methyl-2-(4-aminophenyl)thiazol-5-yl]methanone,s)2-[(4-{5-[3-(3-ethoxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-carbonyl]-4-methylthiazol-2-yl}phenyl)hydrazono]malononitrile,or t)2-[(4-{5-[3-(3-ethoxy-4-methoxyphenyl)-3,4,5,6-tetrahydropyridazin-1-carbonyl]-4-methylthiazol-2-yl}phenyl)hydrazono]-2-(1H-tetrazol-5-yl)acetonitrile,or a pharmaceutically acceptable salt or stereoisomer thereof, or amixture thereof in all ratios.
 2. A pharmaceutical compositioncomprising at least one compound according to claim 1 and/or apharmaceutically usable salt or stereoisomer thereof, including mixturesthereof in all ratios, and a pharmaceutically acceptable carrier.
 3. Amethod of inhibiting proliferation of T-cells in a host in need thereof,comprising administering to said host an effective amount of a compoundof claim 1.